Hypertension: New Concepts,

Guidelines, and Clinical

Management
Nathan D. Wong, PhD, FACC
Associate Professor and Director
Heart Disease Prevention Program
Division of Cardiology, Department of Medicine
College of Medicine, University of California, Irvine

Prevalence of Cardiovascular Disease

Estimated Number of Persons With
Cardiovascular Disease in the US
10

Prevalence (millions)
20
30
40

CHF
Stroke
Other

60

50,000,000

High BP
CAD

50

(24%)

12,200,000
4,600,000
4,400,000
2,800,000

BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure

American Heart Association . 2000 Heart and Stroke Statistical Update. 1999.

Age Distribution of Hypertensives in US

Population
(NHANES III and the 1991 Census)
Hypertensives Within Age
Group (%)

30
25
20
15

26%
47.4 million
hypertensives
26.0% of US
population

23.7
21.3

19.2

13

9.5

10
5

74%

9.6

3.7
18-29

30-39

40-49
50-59
60-69
Age Groups (y)

Franklin SS. J Hypertension. 1999;17(suppl 5):S29-S36.

70-79

80+

Distribution of Hypertension Subtype in the untreated

Hypertensive Population in NHANES III by Age
ISH (SBP 140 mm Hg and DBP <90 mm Hg)
SDH (SBP 140 mm Hg and DBP 90 mm Hg)
IDH (SBP <140 mm Hg and DBP 90 mm Hg)
100

17%

16%

<40

40-49

16%

20%

20%

11%

50-59
60-69
Age (y)

70-79

80+

80
Frequency of
hypertension 60
subtypes in all
untreated
40
hypertensives
(%)
20
0

Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age.
Franklin et al. Hypertension 2001;37: 869-874.

Hypertension: A Significant CV and

Renal Disease Risk Factor
CAD
Stroke

CHF
LVH

Hypertension
Morbidity

Renal
disease
Peripheral vascular
disease

Disability

National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.

Benefits of Lowering BP

Average Percent Reduction

Stroke incidence

3540%

Myocardial infarction

2025%

Heart failure

50%

Preventable CHD Events from Control

of Hypertension in US Adults
(Wong et al., Am Heart J 2003; 145: 888-95)

PAR% = population attributable risk (proportion of CHD events preventable), NNT = number
needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%

Preventable CHD Events from Control

of Hypertension in US Adults
(Wong et al., Am Heart J 2003; 145: 888-95) (cont.)

The greatest impact (absolute numbers) from

control of hypertension occurs in men, older
persons, and those with isolated systolic
hypertension
The greatest proportion of preventable CHD
events from control of hypertension occurs in
women
Optimal control of blood pressure could prevent
more than one third of CHD events in men and
more than half of CHD events in women

BP Control Rates
Trends in awareness, treatment, and control of high
blood pressure in adults ages 1874
National Health and Nutrition Examination Survey,
Percent
II
197680

II
(Phase 1)
198891

II
(Phase 2)
199194

19992000

Awareness

51

73

68

70

Treatment

31

55

54

59

Control

10

29

27

34

Sources: Unpublished data for 19992000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6.

U.S. Department of
Health and Human
Services

National Institutes
of Health

National Heart, Lung, and

Blood Institute

National Heart, Lung, and Blood Institute

National High Blood Pressure Education
Program

The Seventh Report of the

Joint National Committee on
Prevention, Detection,
Evaluation, and Treatment of
High Blood Pressure (JNC 7)

Blood Pressure Classification

BP Classification SBP mmHg
Normal

<120

DBP mmHg
and

<80

Prehypertension

120139

or

8089

Stage 1 Hypertension

140159

or

9099

Stage 2 Hypertension

>160

or

>100

New Features and Key Messages

For persons over age 50, SBP is a more important than
DBP as CVD risk factor
Starting at 115/75 mmHg, CVD risk doubles with each
increment of 20/10 mmHg throughout the BP range.
Persons who are normotensive at age 55 have a 90%
lifetime risk for developing HTN.
Those with SBP 120139 mmHg or DBP 8089 mmHg
should be considered prehypertensive who require
health-promoting lifestyle modifications to prevent
CVD.

4-Year Progression To Hypertension:

The Framingham Heart Study
Participants age 36 and older

(<120/80 mm Hg)

(130/85 mm Hg)

Vasan, et al. Lancet 2001;358:1682-86

(130-139/85-89 mm Hg)

HOT Study: Significant Benefit From

Intensive Treatment in the Diabetic Subgroup
25
20
Major
cardiovascular 15
events/1,000
patient-years
10

p=0.005 for trend

5
0

90

85
Target Diastolic Blood Pressure

Hansson L et al. Lancet. 1998;351:1755-1762.

80

mm Hg

SBP-Associated Risks: MRFIT

SBP versus DBP in Risk of CHD Mortality
80.6

48.3

CHD Death Rate

37.4
34.7

31.
0
2 5 .5

23.8

24.6

16.9

20.6

13.
9
10.3

11.8

38.1

25.2

24.9

12.8

100+
8.8
9099
8.5
8089
7579
Diastolic BP
7074

(mm Hg)

25.3

43.8

12.6

160+

11.8

140159

9.2

120139
<70

<120

Systolic BP
(mm Hg)

Adapted from Neaton JD et al. Arch Intern Med. 1992;152:56-64.

Elevated SBP Alone Is Associated With

Increased Risk of Cardiovascular and
Renal Disease
Disease
Kidney failure (ESRD)
Stroke
Heart failure
Peripheral vascular disease
Myocardial infarction*
Coronary artery disease

Relative Risk
2.8
2.7
1.5
1.8
=1.6
1.5

ESRD = end-stage renal disease; SBP 165 mm Hg.

*Men only.
Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S; Perry HM Jr et al. Hypertension. 1995;25(part 1):587-594;
Klag MJ et al. N Engl J Med. 1996;334:13-18; Nielsen WB et al. Ugeskr Laeger. 1996;158:3779-3783; Neaton JD et al.
Arch Intern Med. 1992;152:56-64.

Lowering SBP Benefits Older

Patients
Clinical trials document importance of
controlling elevated SBP to prevent
cardiovascular disease
SHEP (Systolic Hypertension in the Elderly
Program)
Syst-Eur (Systolic Hypertension in Europe)

Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264; Staessen JA et al. Lancet. 1997;350:757-764.

SHEP: Outcomes
Risk Reduction
Risk Reduction (%)

0
10
13
20
30
40
50

36*

Stroke

Total Mortality

*P=.0003 vs placebo.
Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.

Systolic Hypertension in Europe

(Syst-Eur)
Objective:

To determine whether antihypertensive treatment reduces cardiovascular

complications in older patients with elevated SBP

Patients:

4695 patients, 60 years of age, with SBP 160219 mm Hg

and DBP <95 mm Hg

Treatments: Nitrendipine (1040 mg/day) with possible addition or substitution of:

Enalapril (520 mg/day)
Hydrochlorothiazide (12.525 mg/day)

Placebo
Follow-up: 2 years (median)
Endpoint:

Total stroke
Myocardial infarction

Adapted from Staessen JA et al. Lancet. 1997;350:757-764.

Syst-Eur: Outcomes
Risk Reduction

Percent Reduction

5
10
15
20
25
26

30

29

35

30

31

MI

All Fatal/Nonfatal
Cardiac Endpoints

40
45

42*

Stroke

All Cardiac
Endpoints

Heart
Failure

*P=.003; P=.03; P=.12; P<.001.

Adapted from Staessen JA et al. Lancet. 1997;350:757-764.

Pulse Pressure
PP = SBP DBP
Increase in pulse pressure (PP) indicates greater stiffness
in large conduit arteries, primarily the thoracic aorta.
PP, therefore, is a surrogate measure of dynamic, cyclic
stress during systole.
PP may be a better marker of increased CV risk than either
systolic BP or diastolic BP alone in older persons.

ATP III: The Metabolic Syndrome*

Risk Factor

Defining Level

Abdominal obesity
(Waist circumference)
Men
Women
TG

>102 cm (>40 in)

>88 cm (>35 in)
150 mg/dL

HDL-C

Men
Women

<40 mg/dL
<50 mg/dL

Blood pressure

130/85 mm Hg

Fasting glucose

110 mg/dL

*Diagnosis is established when 3 of these risk factors are present.

Abdominal obesity is more highly correlated with metabolic risk factors than is BMI.

Some men develop metabolic risk factors when circumference is only marginally
increased.
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

2001, Professional Postgraduate Services

www.lipidhealth.org

Prevalence of Selected Risk Factors in US Adults with the Metabolic

Syndrome (without Diabetes)
(Wong et al., Am J Cardiol 2003, in press)

Estimated Proportion of CHD Events Preventable by Control of

Blood Pressure, HDL-C, LDL-C, and All 3 Factors to Optimal
Levels in Persons with the Metabolic Syndrome (Wong et al., Am J
Cardiol 2003, in press)

**

* p<0.05, ** p<0.01 compared to men

ALLHA
T

Antihypertensive
Trial Design

Randomized, double-blind, multi-center clinical

trial
Determine whether occurrence of fatal CHD or
nonfatal MI is lower for high-risk hypertensive
patients treated with newer agents (CCB, ACEI,
alpha-blocker) compared with a diuretic
42,418 high-risk hypertensive patients 55 years

Cumulative Event Rates for the Primary

Outcome (Fatal CHD or Nonfatal MI) by
ALLHAT Treatment Group

ALLHAT
.2

.16

RR (95% CI)

p value

A/C

0.98 (0.90-1.07)

0.65

L/C

0.99 (0.91-1.08)

0.81

Chlorthalidone
Amlodipine
Lisinopril

.12
Cumulative CHD Event Rate
.08

.04

0
0
Number at Risk:
Chlorthalidone
Amlodipine
Lisinopril

15,255
9,048
9,054

1
14,477
8,576
8,535

2
13,820
8,218
8,123

3
4
Years to CHD Event
13,102
7,843
7,711

11,362
6,824
6,662

5
6,340
3,870
3,832

6
2,956
1,878
1,770

7
209
215
195

ALLHAT
.1

.08

Cumulative Event Rates for Stroke by

ALLHAT Treatment Group
RR (95% CI)

p value

A/C

0.93 (0.81-1.06)

0.28

L/C

1.15 (1.02-1.30)

0.02

.06

Chlorthalidone
Amlodipine
Lisinopril

Cumulative Stroke Rate

.04

.02

0
0
Number at risk:
Chlor
15,255
Amlo
9,048
Lisin
9,054

1
14,515
8,617
8,543

2
13,934
8,271
8,172

3
4
Years to Stroke
13,309
7,949
7,784

11,570
6,937
6,765

5
6,385
3,845
3,891

6
3,217
1,813
1,828

7
567
506
949

Cumulative Event Rates for Heart

Failure by ALLHAT Treatment Group

ALLHA
T
.15

HR (95% CI)

p value

A/C

1.38 (1.25-1.52)

<.001

L/C

1.19 (1.07-1.31)

<.001

.12
Chlorthalidone
Amlodipine
Lisinopril

.09
Cumulative CHF Rate
.06
.03
0
0
Number at risk:
Chlor
15,255
Amlo
9,048
Lisin
9,054

14,528
8,535
8,496

13,898
8,185
8,096

3
4
Years to HF
13,224
7,801
7,689

11,511
6,785
6,698

5
6,369
3,775
3,789

6
3,016
1,780
1,837

7
384
210
313

ALLHAT

Overall Conclusions

Because of the superiority of thiazide-type

diuretics in preventing one or more major forms
of CVD and their lower cost, they should be the
drugs of choice for first-step antihypertensive
drug therapy.

JNC-VII New Features and Key

Messages (Continued)
Thiazide-type diuretics should be initial drug therapy
for most, either alone or combined with other drug
classes.
Certain high-risk conditions are compelling
indications for other drug classes.
Most patients will require two or more
antihypertensive drugs to achieve goal BP.
If BP is >20/10 mmHg above goal, initiate therapy
with two agents, one usually should be a thiazidetype diuretic.

JNC-VII New Features and Key

Messages (Continued)
The most effective therapy prescribed by the careful clinician
will control HTN only if patients are motivated.
Motivation improves when patients have positive experiences
with, and trust in, the clinician.
Empathy builds trust and is a potent motivator.
The responsible physicians judgment remains paramount.

Patient Evaluation
Evaluation of patients with documented HTN has three
objectives:
1. Assess lifestyle and identify other CV risk factors or
concomitant disorders that affects prognosis and guides
treatment.
2. Reveal identifiable causes of high BP.
3. Assess the presence or absence of target organ damage
and CVD.

BP Measurement Techniques
Method
In-office

Brief Description

Ambulatory BP
monitoring

Indicated for evaluation of white-coat

HTN. Absence of 1020% BP decrease
during sleep may indicate increased CVD
risk.

Self-measurement

Provides information on response to

therapy. May help improve adherence to
therapy and evaluate white-coat HTN.

Two readings, 5 minutes apart, sitting in

chair. Confirm elevated reading in
contralateral arm.

CVD Risk Factors

Hypertension*
Cigarette smoking
Obesity* (BMI >30 kg/m2)
Physical inactivity
Dyslipidemia*
Diabetes mellitus*
Microalbuminuria or estimated GFR <60 ml/min
Age (older than 55 for men, 65 for women)
Family history of premature CVD
(men under age 55 or women under age 65)
*Components of the metabolic syndrome.

JNC VI: BP Risk Stratification

Risk Group A
No CV risk factors
No diabetes, target-organ damage, or clinical CVD

Risk Group B
At least one other risk factor: age >60, male gender or
postmenopausal status, dyslipidemia, smoking, +FH

(No diabetes, target-organ damage, or clinical CVD)

Risk Group C
Diabetes or target-organ damage or clinical CVD
with or without other risk factors
JNC VI. Arch Intern Med 1997;157:2413.

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

Laboratory Tests
Routine Tests
Electrocardiogram
Urinalysis
Blood glucose, and hematocrit
Serum potassium, creatinine, or the corresponding estimated GFR,
and calcium
Lipid profile, after 9- to 12-hour fast, that includes high-density and
low-density lipoprotein cholesterol, and triglycerides
Optional tests
Measurement of urinary albumin excretion or albumin/creatinine ratio
More extensive testing for identifiable causes is not generally indicated unless BP
control is not achieved

Lifestyle Modification
Modification
Weight reduction
Adopt DASH eating plan
Dietary sodium reduction

Approximate SBP reduction

(range)
520 mmHg/10 kg weight loss
814 mmHg
28 mmHg

Physical activity

49 mmHg

Moderation of alcohol
consumption

24 mmHg

Lifestyle Modifications
For Prevention and
Management

For Overall and

Cardiovascular Health

Lose weight if overweight

Limit alcohol intake

Maintain adequate intake

of calcium and magnesium
Stop smoking

Increase aerobic physical

activity
Reduce sodium intake
Maintain adequate intake
of potassium

Reduce dietary saturated

fat and cholesterol

Dietary Approaches to Stop

Hypertension (DASH)
Diet high in fruits and vegetables and low-fat dairy
products lowers blood pressure (11 mmHg SBP/ 5
mmHg DBP lower than traditional US diet),
including more than a sodium-restricted diet
Recommends 7-8 servings/day of grain/grain
products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat
dairy products, 2 or less meat, poultry, and fish.
NEJM 1997; 366: 1117-24.

Algorithm for Treatment of Hypertension

Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling
Indications

With Compelling
Indications

Stage 1 Hypertension

Stage 2 Hypertension

(SBP 140159 or DBP 9099 mmHg)

Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.

(SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)

Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.

Drug(s) for the compelling

indications
Other antihypertensive drugs (diuretics,
ACEI, ARB, BB, CCB)
as needed.

Classification and Management

of BP for adults
BP
SBP* DBP*
classificatio
mmHg mmHg
n

Lifestyle
modificati
on

Normal

<120 &

<80

Encourage

Prehypertensi
on

120
139

or 80
89

Yes

Stage 1
Hypertension

140
159

or 90
99

Yes

Initial drug therapy

Without compelling
indication

No antihypertensive
drug indicated.

With compelling
indications

Drug(s) for
compelling
indications.

Thiazide-type diuretics
for most. May consider Drug(s) for the
ACEI, ARB, BB, CCB, or compelling
indications.
combination.
Other
Two-drug combination for
Stage 2
>160 or >100
Yes
antihypertensive
most (usually thiazide-type
Hypertension
diuretic and ACEI or ARB or drugs (diuretics,
*Treatment determined by highest BP category.
BB or CCB).
ACEI, ARB, BB,
Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.
CCB) as needed.

Followup and Monitoring

Patients should return for followup and adjustment of medications
until the BP goal is reached.
More frequent visits for stage 2 HTN or with complicating comorbid
conditions.
Serum potassium and creatinine monitored 12 times per year.

Followup and Monitoring

(continued)
After BP at goal and stable, followup visits at 3- to 6-month intervals.
Comorbidities, such as heart failure, associated diseases, such as
diabetes, and the need for laboratory tests influence the frequency
of visits.

Special Considerations
Compelling Indications
Other Special Situations
Minority populations
Obesity and the metabolic syndrome
Left ventricular hypertrophy
Peripheral arterial disease
Hypertension in older persons
Postural hypotension
Dementia
Hypertension in women
Hypertension in children and adolescents
Hypertension urgencies and emergencies

Compelling Indications for

Individual Drug Classes
Compelling Indication Initial Therapy

Heart failure

Clinical Trial Basis

THIAZ, BB, ACEI, ARB, ACC/AHA Heart Failure

Guideline, MERIT-HF,
ALDO ANT
COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE,
ValHEFT, RALES

Postmyocardial
infarction

BB, ACEI, ALDO ANT

THIAZ, BB, ACE, CCB

High CAD risk

ACC/AHA Post-MI
Guideline, BHAT, SAVE,
Capricorn, EPHESUS
ALLHAT, HOPE, ANBP2,
LIFE, CONVINCE

Compelling Indications for

Individual Drug Classes
Compelling Indication Initial Therapy
Options
THIAZ, BB, ACE, ARB,
Diabetes
CCB

Clinical Trial Basis

NKF-ADA Guideline,
UKPDS, ALLHAT

Chronic kidney
disease

ACEI, ARB

NKF Guideline,
Captopril Trial,
RENAAL, IDNT,
REIN, AASK

Recurrent stroke
prevention

THIAZ, ACEI

PROGRESS

Cardiovascular Diseases
Cerebrovascular disease
Indication for treatment, except immediately after
ischemic cerebral infarction.

Coronary artery disease

Benefits of therapy well established.

Left ventricular hypertrophy

Antihypertensive agents (except direct vasodilators)
indicated.
Reduced weight and decreased sodium intake
beneficial.

Cardiovascular
Diseases (continued)
Cardiac failure
ACE inhibitors, especially with digoxin or
diuretics, shown to prevent subsequent heart
failure.

Peripheral arterial disease

Limited or no data available.

Relative Risk of CV Events and Mortality:

CCBs vs Diuretics or Beta Blockers
No. of Events*
CCBs
(n=11,685)

Stroke
CHD
Heart Failure
Major CV Events
CV Death
Total Mortality

456
567
278
1,251
425
776

Diuretics or
Beta Blockers
(n=11,769)

Relative Risk
(95% CI)

529
510
250
1,234
405
776
0.5

1.0

Relative Risk

0.87 (0.77-0.98)
1.12 (1.00-1.26)
1.12 (0.95-1.33)
1.02 (0.95-1.10)
1.05 (0.92-1.20)
1.01 (0.92-1.11)
2.0

CCBs, calcium channel blockers.

Favors CCBs
Favors diuretics or beta blockers
CHD, coronary heart disease.
* Includes INSIGHT, NICS-EH, STOP-2, NORDIL, and VHAS.
Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk.
Adapted from Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2000;356:1955-1964.

HOPE: Risk Reduction of CV Events

Associated with ACEI (RAS Inhibition) Treatment

MI, Stroke,
CV Death
(primary
end point)

CV Death

MI

Stroke

All-cause
Death

Risk Reduction (%)

-5
-10
-15
-20
-25
-30
-35

-22
(P<.001)

-16
(P=.005)

-20
(P<.001)
-26
(P<.001)
-32
(P<.001)

Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting
enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

Relative Risk of CV Events and Mortality:

ACE Inhibitors vs Diuretics or Beta Blockers
No. of Events*
Diuretics or
ACE Inhibitors Beta Blockers
(n=8,064)
(n=8,097)

Stroke
CHD
Heart Failure
Major CV Events
CV Death
Total Mortality

425
423
223
1,018
350
639

Relative Risk
(95% CI)

402
420
250
1,004
348
618
0.5

1.0

Relative Risk

Favors ACE inhibitors

1.05 (0.92-1.19)
1.00 (0.88-1.14)
0.92 (0.77-1.09)
1.00 (0.93-1.08)
1.00 (0.87-1.15)
1.03 (0.93-1.14)
2.0

Favors diuretics or beta blockers

CHD, coronary heart disease.

* Includes STOP-2, UKPDS-HDS, and CAPPP.
Diamonds represent the 95% CI for pooled estimates of effect and are centered on pooled relative risk.
Adapted from Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2000;356:1955-1964.

Reversal of LV Hypertrophy By
Antihypertensive Treatment
Change in LV mass index
(%)

Diuretics

Calcium
channel
blockers

-blockers

ACE
inhibitors

-5
-10

7%

6%
9%
13%

-15
p<.01

-20
p<.01

-25

Schmieder RE et al. JAMA. 1996;275:1507-1513.

Regressors (n=52)

90
80

P=.002

70
60

Nonregressors (n=50)
50

Rate of events
(per 100 patient-yrs)

Probability of event-free survival

(%)

100

Regression of LV Hypertrophy
Predicts Prognosis 7
5
4
3
2
1
0

0
0

100

200 300 400 500

Time to event (wk)

Regressors (n=285)
Nonregressors (n=145)

LV, left ventricular.

Nonregressors defined as baseline and follow-up left ventricular mass index (LVMI) >125 g/m 2;
regressors defined as baseline LVMI >125 g/m 2 and follow-up LVMI <125 g/m2.
Adapted from Verdecchia P et al. Circulation. 1998;97:48-54.

Irbesartan and Atenolol in

Hypertension and LVH
Study Design

Irbesartan
150-300 mg
Single-blind
Placebo

Double
Blind

Addition of
Felodipine
5-10 mg
if SeDBP
90 mm Hg

Addition of HCTZ
12.5-25 mg
if SeDBP
90 mm Hg

Atenolol
50-100 mg

Wk: -4

12

24

48

* BP, echocardiography, neurohormone measurements.

Malmqvist K et al. J Hypertens. 2001;19:1167-1176.

Irbesartan vs Atenolol in Hypertension and

LVH: SeDBP Reduction
12 wk

% reduction in SeDBP

24 wk

48 wk

-5
-10

*
*

-15

*
*
*

-20
Irbesartan
* p<.001 vs baseline.

p<.028 irbesartan vs atenolol.

Malmqvist K et al. J Hypertens. 2001;19:1167-1176.

Atenolol

Irbesartan vs Atenolol in Hypertension and LVH:

LVMI Reduction
0

12 wk

24 wk

48 wk

% change in LVMI (g/m2)

-2
-4
-6
-8

-10

-12

-14
-16
-18

Irbesartan
*p<.001 vs baseline; p=.024 irbesartan vs atenolol.
Malmqvist K et al. J Hypertens. 2001;19:1167-1176.

Atenolol

LIFE: Inclusion Criteria

Age 55-80 years
Previously treated or untreated
hypertension
Systolic BP 160-200 mmHg or
Diastolic BP 95-115 mmHg
ECG LVH
Adapted from Dahlf B et al. Am J Hypertens. 1997;10:705-13.

LIFE: Dosing
Titration to target blood pressure: <140 / <90 mmHg
Losartan 100 mg + HCTZ 12.5-25 mg + others*
Losartan 100 mg + HCTZ 12.5 mg
Losartan 50 mg + HCTZ 12.5 mg
Placebo
Run-in

Losartan 50 mg
Atenolol 50 mg
Atenolol 50 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5-25 mg + others*

Average follow up

4.7 years

* Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers.

Adapted from Dahlf B et al. Am J Hypertens. 1997;10:705-713.

LIFE: Blood Pressure Results Follow-up

180
Atenolol
Losartan

160

Atenolol 145.4 mmHg

Systolic

mmHg

140

Losartan 144.1 mmHg

120
Mean Arterial

100

Losartan 81.3 mmHg

80

Diastolic

Atenolol 80.9 mmHg

60
40

12

18

B Dahlf et al. Lancet. 2002;359:995-1003.

24
30
Study Month

36

42

48

54

LIFE: Primary and

Select Secondary Outcomes
LosartanAtenolol
Adjusted*
(n=4,605) (n=4,588) RR (%) p-value
Primary composite

508

588

-13

.021

CV mortality

204

234

-11

.21

Stroke

232

309

-25

.001

MI 198

188

+7

.49

Total mortality

383

431

-10

.13

New onset DM

241

319

-25

<.001

* For degree of LVH and Framingham risk score at randomization

Number of patients with a first primary event
In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979)
Adapted from B Dahlf et al. Lancet. 2002;359:995-1003.

Valsartan Heart Failure Trial

(Val-HeFT)
Study Characteristics:
5,010 total patients randomized with NYHA class II, III, or IV
HF
Two groups: valsartan (target dose 160 mg BID) plus
standard therapy vs placebo plus standard therapy
Mean duration of follow-up: 23 months (range 0-38)
Two primary end points:
Mortality
Combined mortality and morbidity (morbidity defined as cardiac
arrest with resuscitation, hospitalization for HF, or administration of
IV inotropic or vasodilator drugs for > 4 hours without hospitalization)

Val-HeFT
Results
Overall mortality was similar in the two groups
13% RRR (p=.009) in combined end point
Predominantly because of a 27% decrease in hospitalization for
HF in the valsartan group
Subgroup analyses:
Valsartan had a favorable effect in patients receiving neither an ACE
inhibitor nor a beta-blocker
Valsartan had a favorable effect in patients receiving an ACE inhibitor or a
beta blocker
Valsartan demonstrated a statistically non-significant trend towards an
adverse outcome in patients receiving an ACE inhibitor and a beta blocker

Web site
www.nhlbi.nih.gov/

DASH Fact Sheet

Your Guide to Lowering

Blood Pressure

Reference Card

Diabetes Mellitus
Drug therapy should begin along with lifestyle
modifications to reduce blood pressure to
< 130/85 mm Hg.
ACE inhibitors, -blockers, calcium antagonists, and
low-dose diuretics are preferred.
Insulin resistance or high peripheral insulin levels may
cause hypertension, which can be treated with lifestyle
changes, insulin-sensitizing agents, vasodilating
antihypertensive drugs, and lipid-lowering agents.

Renal Disease
Hypertension may result from renal disease that
reduces functioning nephrons.
Evidence shows a clear relationship between high
blood pressure and end-stage renal disease.
Blood pressure should be controlled to < 130/85 mm
Hg or lower (< 125/75 mm Hg) in patients with
proteinuria in excess of 1 gram per 24 hours.
ACE inhibitors work well to control blood pressure
and slow progression of renal failure.

ADA Guidelines on Management of

Diabetic Nephropathy
Hypertensive Type 2 Diabetic Patients*
ARBs

are the initial agents of choice

Type 1 Diabetics with or without
hypertension*
ACEIs

are the initial agents of choice

If one class is not tolerated the other should
be substituted
* With microalbuminuria and clinical proteinuria.
Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.

MRFIT: Association of Systolic BP and

Cardiovascular Death in Type 2 Diabetes
250
225
200

Nondiabetic
Diabetic

175
Cardiovascular
150
mortality
rate/10,000 125
person-yr
100
75
50
25
0

< 120

120139

140159

160179

180199

Systolic blood pressure (mm Hg)

Stamler J et al. Diabetes Care. 1993;16:434-444.

200

Veterans Administration
Hypertension and Screening Clinics
15-Year ESRD Rates and Risk Ratios by Baseline
Systolic Blood Pressure
SBP (mm Hg)
Risk Ratio
< 140
> 140 but < 151
> 151 but < 165
> 165 but < 180
> 180

1.00
1.00
1.08
2.07
5.62

Number of screenees: 11,912 (5,730 black; 6,182 white)

Source: Perry HM, et al. Hypertension. 1995;25:587-594

Veterans Administration
Hypertension and Screening
Clinics
15-Year ESRD Rates and Risk Ratios by Baseline
Diastolic Blood Pressure
DBP (mm Hg)
< 94
> 94 but < 100
> 100 but < 106
> 106 but < 118
> 118

Risk Ratio
1.00
1.05
0.89
1.54
4.18

Number of screenees: 11,912 (5,730 black; 6,182 white)

Source: Perry HM, et al. Hypertension. 1995;25:587-594

United Kingdom Prospective Diabetes

Study (UKPDS): Results
Tight blood pressure control* with captoprilor atenolol-based therapy reduces risk of

Risk reduction

p-value

Any diabetes-related endpoints

24%

0.005

Diabetes-related deaths

32%

0.019

Stroke

44%

0.013

Microvascular endpoints

37%

0.009

* Mean blood pressure achieved: 144/82 vs 154/87 mm Hg.

UK Prospective Diabetes Study Group 38. BMJ. 1998;317:703-713.
UK Prospective Diabetes Study Group 33. Lancet. 1998;352:837-853.

Diabetic Nephropathy
Burden of Illness
Incidence
Approximately 40% of all new cases of ESRD in the U.S. are due to
diabetes1
Type 2 diabetes accounts for most cases of diabetic nephropathy 2,3
Prevalence of nephropathy 57% after 25 years of type 2 diabetes 4
Cost

In U.S. alone, total annual spending for ESRD > $15 billion1
Cost/patient-year higher for diabetic ESRD ($51,000) than
nondiabetic ESRD ($39,000)5

1. USRDS Coordinating Center. USRDS 1999 Annual Data Report. The Kidney Epidemiology and Cost Center of the
University of Michigan; 1999. NIH Contract no. NO1-DK-3-2202.
2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72.

Diabetic Nephropathy
Burden of Illness (continued)
Mortality
1.5-2.5x

greater mortality among diabetics with

ESRD than nondiabetics1
< 20% of diabetics with ESRD survive 5 years
after initiation of dialysis1
Cardiovascular complications the most common
cause of death2,3

1. Koch M et al. Diabetologia. 1993;36:1113-1117.

2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42.
3. Grundy SM et al. Circulation. 1999;100:1134-1146.

Correlation Between MAP &

Renal Function
MAP (mm Hg)
95

98

101

104

107

110

113

116

119

0
r=0.69; P<.05

GFR Decline
(mL/min/y)

-2
-4
-6

Untreated
HTN

-8
-10
-12
-14

130/85

140/90

GFR, glomerular filtration rate; HTN, hypertension; MAP, mean arterial pressure.
Adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

Microalbuminuria as a Risk Factor

for Death in Type 2 Diabetes
1.0

Survival

0.8
0.6
0.4

UAC 15 g/mL
UAC 16-40 g/mL

0.2

UAC 41-200 g/mL

0.0
0

4
5
6
7
Years after Diagnosis

UAC, urinary albumin concentration.

Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134.

10

11

40

1.0

P<.001 for trends

0.9

0.8
0.7
0.6
0.5
0

B
P-values:
Overall <.001
A vs B =.013
A vs C <.001
B vs C <.001

Incidence (%)

Reduction in Survival due

to CV Mortality

Proteinuria & Risk of CV

Mortality,Stroke, & CHD Events in
Type 2 Diabetes
30
20
10
0

0 10 20 30 40 50 60 70 80 90

Stroke

CHD Events*

Months
A: UPC <150 mg/L

B: UPC 150-300 mg/L

CHD, coronary heart disease; UPC, urinary protein concentration.

* Defined as CHD death or nonfatal MI.
Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.

C: UPC >300 mg/L

Risk Reduction of Diabetes-Related

End Points with Tight BP Control

Risk Reduction (%)

Diabetes-related
Mortality*

Stroke

Microvascular
End Points

Myocardial
Infarction

10
20

21

30
32
37

40
50

44

* Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or
hypoglycemia.
Fatal or nonfatal.

HOT: Significant Benefit From Intensive

Antihypertensive Treatment in Diabetes
Major CV Events*/1000
Patient-yrs in Hypertensive
Patients with Diabetes

25
20
15

P=.005 for trend

10
5
0

90

85
Target DBP (mm Hg)

* Defined as fatal and nonfatal MI, fatal and nonfatal stroke, and all other CV death.
Adapted from Hansson L et al. Lancet. 1998;351:1755-1762.

80

Progression to Death, Dialysis,

or Transplant (%)

Effect of ACE Inhibition on

Nephropathy in Type 1 Diabetes
40

30

Placebo

20
*
10

0
0

2
Follow-up (y)

* P=.006 vs placebo.
Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.

Captopril

Mean SeSBP and SeDBP

(mm Hg)

IRMA 2: Blood Pressure

Response
160
150
140
130
120
110
100
90
80
70
0

Control SeSBP*
Irbesartan 150 mg SeSBP*
Irbesartan 300 mg SeSBP*

Control SeDBP*
Irbesartan 150 mg SeDBP*
Irbesartan 300 mg SeDBP*

12
15
Months

18

21

24

27

SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure.
Control defined as placebo.
* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added

IRMA 2 Primary Endpoint

Development of Overt Proteinuria
18
16

14.9

RRR=70%
P<0.001
RRR=39%
P=0.08

14
Subjects
(%)

12
9.7

10
8
6

5.2

4
2
0

Control
(n=201)

Parving H-H, et al. N Engl J Med 2001;345:870-878.

150 mg
(n=195)

300 mg
(n=194)
Irbesartan

IDNT: Systolic BP, Mean Arterial Pressure, &

Diastolic BP Response
160

SBP

BP (mm Hg)

140

Irbesartan
Amlodipine
Control

120

MAP
100

DBP

80
0

12

18

24

30

36

42

48

54

Follow-up Visit (mo)

Control defined as placebo.
Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups,
and 3.3 concomitant agents in the control group.

IDNT Primary Endpoint:

Time to Doubling of Serum Creatinine, ESRD, or Death

70
Irbesartan
RRR 23%
P=0.006

60
Amlodipine
50
Subjects
(%)

P=NS

RRR 20%
P=0.02

Control
40
30
20
10
0
0

12

18

Lewis EJ et al. N Engl J Med 2001;345:851-860.

24

30

36

Follow-up (mo)

42

48

54

60

IDNT & RENAAL:

Study
Design
IDNT
RENAAL

IDNT

Patients:
& nephropathy
Treatment arms:

1,715 HTN patients with type 2 1,513 HTN patients with

type 2 diabetes &
nephropathy
irbesartan, amlodipine,
losartan, placebo
placebo

Target BP:
Adjunctive therapy:
inhibitors, or CCBs
Primary outcome:
ESRD, or death
Secondary outcomes:

135/85 mm Hg
Permitted except ARBs,
CCBs, except ARBs or
Composite of doubling of
SeCr, ESRD, or death
CV events

SeCr, serum creatinine; ESRD, end-stage renal disease.

Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Brenner BM et al. N Engl J Med. 2001;345:861-869.

140/90 mm Hg
Permitted including
ACE inhibitors
Composite of doubling of
CV events

diabetes

ACE
SeCr,

IDNT and RENAAL Trial Results

Comparison of Major Endpoints
RRR (%)
RENAAL
Losartan vs
control

IDNT
Irbesartan vs
control

Irbesartan vs
amlodipine

Amlodipine
vs control

Doubling of Creat,
ESRD, or death

16 (P=0.02)

20 (P=0.02)

23 (P=0.006)

-4 (P=0.69)

Doubling of Creat

25 (P=0.006)

33 (P=0.003)

37 (P<0.001)

-6 (P=0.60)

ESRD

28 (P=0.002)

23 (P=0.07)

23 (P=0.07)

0 (P=0.99)

Death

-2 (P=0.88)

8 (P=0.57)

-4 (P=0.8)

12 (P=0.4)

CV Morbidity
& Mortality

10 (P=0.26)

9 (P=0.4)

-3 (P=0.79)

12 (P=0.29)

Lewis EJ et al. N Engl J Med 2001;345:851-860.

Brenner B et al. N Engl J Med 2001;345:861-869.

Minority Populations
In general, treatment similar for all demographic groups.
Socioeconomic factors and lifestyle important barriers to BP control.
Prevalence, severity of HTN increased in African Americans.
African Americans demonstrate somewhat reduced BP responses to
monotherapy with BBs, ACEIs, or ARBs compared to diuretics or
CCBs.
These differences usually eliminated by adding adequate doses of a
diuretic.

Left Ventricular Hypertrophy

LVH is an independent risk factor that increases the risk of CVD.
Regression of LVH occurs with aggressive BP management: weight
loss, sodium restriction, and treatment with all classes of drugs
except the direct vasodilators hydralazine and minoxidil.

Peripheral Arterial Disease

(PAD)
PAD is equivalent in risk to ischemic heart disease.
Any class of drugs can be used in most PAD patients.
Other risk factors should be managed aggressively.
Aspirin should be used.

Hypertension in Older
Persons
More than two-thirds of people over 65 have HTN.
This population has the lowest rates of BP control.
Treatment, including those who with isolated systolic HTN, should
follow same principles outlined for general care of HTN.
Lower initial drug doses may be indicated to avoid symptoms;
standard doses and multiple drugs will be needed to reach BP
targets.

Postural Hypotension
Decrease in standing SBP >10 mmHg, when associated with
dizziness/fainting, more frequent in older SBP patients with diabetes,
taking diuretics, venodilators, and some psychotropic drugs.
BP in these individuals should be monitored in the upright position.
Avoid volume depletion and excessively rapid dose titration of drugs.

Dementia
Dementia and cognitive impairment occur more commonly in people
with HTN.
Reduced progression of cognitive impairment occurs with effective
antihypertensive therapy.

Hypertension in Women
Oral contraceptives may increase BP, and BP should be checked
regularly. In contrast, HRT does not raise BP.
Development of HTNconsider other forms of contraception.
Pregnant women with HTN should be followed carefully. Methyldopa,
BBs, and vasodilators, preferred for the safety of the fetus. ACEI and
ARBs contraindicated in pregnancy.

Strategies for Improving

Adherence to Regimens
Clinician empathy increases patient trust, motivation, and
adherence to therapy.
Physicians should consider their patients cultural beliefs
and individual attitudes in formulating therapy.

Causes of
Resistant Hypertension
Improper BP measurement
Excess sodium intake
Inadequate diuretic therapy
Medication
Inadequate doses
Drug actions and interactions (e.g., nonsteroidal anti-inflammatory
(NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)
Over-the-counter (OTC) drugs and herbal supplements
Excess alcohol intake
Identifiable causes of HTN

drugs

Public Health Challenges

and Community Programs
Public health approaches (e.g. reducing calories, saturated fat, and
salt in processed foods and increasing community/school
opportunities for physical activity) can achieve a downward shift in the
distribution of a populations BP, thus potentially reducing morbidity,
mortality, and the lifetime risk of an individuals becoming
hypertensive.
These public health approaches can provide an attractive opportunity
to interrupt and prevent the continuing costly cycle of managing HTN
and its complications.

Supporting Materials
Web site www.nhlbi.nih.gov/
For patients and the general public
Facts About the DASH Eating Plan (Revised May 2003)
Your Guide to Lowering Blood Pressure
For health professionals
Reference Card
Slide Show

Back-up Slides: Special

Populations
Racial and ethnic groups
Children and adolescents
Women
Older persons

Potential Pathogenic Properties

of Angiotensin II
Heart
Myocardial hypertrophy
Interstitial fibrosis
Coronary Arteries
Endothelial dysfunction with decreased release of nitric oxide
Coronary constriction via release of norepinephrine
Formation of oxygen-derived free radicals via NADH (nicotinamide
adenine dinucleotide) oxidase
Promotion of inflammatory response and plaque instability
Promotion of low-density lipoprotein cholesterol uptake

Adapted from Opie and Gersh. Drugs for the Heart, 2001.

Potential Pathogenic Properties

of Angiotensin II (continued)
Kidneys

Increased intraglomerular pressure

Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow

Adrenal Glands
Increased formation of aldosterone

Coagulation System
Increased fibrinogen
Increased PAI-1 (plasminogen activator inhibitor-1) relative to tissue
plasminogen factor
Adapted from Opie and Gersh. Drugs for the Heart, 2001.

Summary of Chapter 3 (continued)

Management strategies can improve adherence
through the use of multidisciplinary teams.
The reductions in cardiovascular events
demonstrated in randomized controlled trials have
important implications for managed care
organizations.
Management of hypertensive emergencies requires
immediate action, whereas urgencies benefit from
reducing blood pressure within a few hours.

Drug Therapy
A low dose of initial drug should be used,
slowly titrating upward.
Optimal formulation should provide 24-hour
efficacy with once-daily dose with at least
50% of peak effect remaining at end of 24
hours.
Combination therapies may provide additional
efficacy with fewer adverse effects.

Classes of
Antihypertensive Drugs
ACE inhibitors
Adrenergic inhibitors
Angiotensin II receptor blockers
Calcium antagonists
Direct vasodilators
Diuretics

Combination Therapies
-adrenergic blockers and diuretics
ACE inhibitors and diuretics
Angiotensin II receptor antagonists and
diuretics
Calcium antagonists and ACE inhibitors
Other combinations

Followup
Followup within 1 to 2 months after initiating therapy.
Recognize that high-risk patients often require high
dose or combination therapies and shorter intervals
between changes in medications.
Consider reasons for lack of responsiveness if blood
pressure is uncontrolled after reaching full dose.
Consider reducing dose and number of agents after
1 year at or below goal.

Guidelines for Improving

Adherence to Therapy
Be aware of signs of nonadherence.
Establish goal of therapy.
Encourage a positive attitude about achieving
goals.
Educate patients about the disease and therapy.
Maintain contact with patients.
Encourage lifestyle modifications.
Keep care inexpensive and simple.

Guidelines for Improving

Adherence to Therapy (continued)
Integrate therapy into daily routine.
Prescribe long-acting drugs.
Adjust therapy to minimize adverse effects.
Continue to add drugs systematically to meet
goal.
Consider using nurse case management.
Utilize other health professionals.
Try a new approach if current regime is
inadequate.

Racial and Ethnic Groups

African Americans

Among the highest prevalence

Early onset
Delayed treatment

Hispanics

Generally low prevalence

Lowest control rate in Mexican Americans

Asian and
Pacific Islanders

May be more responsive to

treatment than other groups

American Indians

Similar prevalence to general population

High prevalence of diabetes and obesity

Women
Clinical trials have not demonstrated
significant differences between men and
women in treatment response and outcomes.
Some women using oral contraceptives may
have significant increases in blood pressure.
High blood pressure is not a contraindication
to hormone replacement therapy.

Pregnant Women
Chronic hypertension is high blood pressure present
before pregnancy or diagnosed before the 20th week
of gestation.
Preeclampsia is increased blood pressure that occurs
in pregnancy (generally after the 20th week) and is
accompanied by edema, proteinuria, or both.
ACE inhibitors and angiotensin II receptor blockers
are contraindicated for pregnant women.
Methyldopa is recommended for women diagnosed
during pregnancy.

Antihypertensive Drugs
Used in Pregnancy
These agents* may be used with chronic hypertension
(DBP > 100 mm Hg) or acute hypertension (DBP > 105 mm Hg).
Central -agonists Methyldopa is the drug of choice.
-blockers and
--blockers

Atenolol, metoprolol, and labetalol appear

safe and effective in late pregnancy.

Calcium
antagonists

Potential synergism with magnesium sulfate

may lead to precipitous hypotension.

*Limited or no controlled trials in pregnant women.

Antihypertensive Drugs
Used in Pregnancy (continued)
These agents* may be used with chronic hypertension
(DBP > 100 mm Hg) or acute hypertension (DBP > 105).
Diuretics

Diuretics are recommended for chronic

hypertension if prescribed before gestation, but
they are not recommended for preeclampsia.

Direct
vasodilators

Hydralazine is the parenteral drug of choice based

on its long history of safety and efficacy.

*Limited or no controlled trials in pregnant women.

ACE inhibitors and angiotensin II receptor blockers are contraindicated.

Older Persons
Hypertension is common.
SBP is a better predictor of events than DBP.
Pseudohypertension and white-coat
hypertension may indicate a need for readings
outside the office.
Primary hypertension is the most common
cause, but common identifiable causes
(e.g., renovascular hypertension) should be
considered.

Older Persons (continued)

Therapy should begin with lifestyle
modifications.
Starting doses for drug therapy should be
lower than those used in younger adults.
Goal of therapy is the same (< 140/90 mm Hg),
although an interim goal of SBP < 160 mm Hg
may be necessary.

Combined Results of Five

Randomized Trials of Antihypertensive
Treatment in the Elderly
Total numbers of individuals affected

600
500

T = Treatment
C = Control
= Fatal events

400

494

438

438

C
346

300

288

C
383
T

279

362
T

344
C

T
208

200
120

100
0

78

Stroke

% (SD) reduction
34% (6)
in odds
2P <0.0001

CHD

Vascular
deaths

All other
deaths

19% (7)
2P <0.05

23% (6)
2P <0.001

7% (8)
2P >0.5

Effects of Therapy in Elderly

Hypertensive Patients

Mean BP
at entry (mm Hg)

SHEP
(1991)

STOP-HTN
(Dahlf, 1991)

MRC
(1992)

SYST-EUR
(1997)

170/77

195/102

185/91

174/85

IRMA 2: Study Design

590 patients with hypertension, type 2 diabetes, microalbuminuria
(albumin excretion rate 20200 g/min), and normal renal function

Double-blind Treatment
Placebo/Control group*

Screening/Enrollment
Up to 5
weeks

Irbesartan 150 mg*

Irbesartan 300 mg*

Follow-up: 2 years

* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and
dihydropyridine calcium channel blockers) could be added to all groups to help achieve equal blood pressure levels.
Parving H-H, et al. N Engl J Med 2001;345:870-878.

Mechanism of Action of
Angiotensin II Receptor Antagonists
Angiotensinogen
Bradykinin

Inactive
peptides

Angiotensin I
Angiotensin II

AIIRAs

AT2

ACE
inhibitors

Alternate
pathways

pt o
e
c
e
r

Vasodilation
Attenuate growth and
disease progression

AT1 receptor

Ot h
e
rece r AT
ptor
s

IRMA 2: Clinical Outcome Measures

Primary outcome:
Time to occurrence of overt proteinuria (AER > 200
g/min)

Secondary outcomes:

Change in AER
Regression to normoalbuminuria (AER < 20 g/min)
Change in creatinine clearance
Clotting factors and lipid profile

Parving H-H, et al. N Engl J Med 2001;345:870-878.

IDNT: Study Design

1,715 patients with hypertension, type 2 diabetes, and
proteinuria 900 mg/day
Double-blind Treatment
Screening/Enrollment

Irbesartan*
Placebo/Control group*

Up to 5
weeks
* Adjunctive antihypertensive therapies (excluding ACE
inhibitors, angiotensin II receptor antagonists, and
calcium channel blockers) could be added to all groups
to help achieve equal blood pressure levels.
Lewis EJ et al. N Engl J Med 2001;345:851-860.

Amlodipine*

Minimum follow-up:
approximately 2 years
(average follow-up 2.6 years)

IDNT
Clinical Outcome Measures
Primary outcome is time to a composite endpoint consisting
of:
Doubling of baseline serum creatinine
End-stage renal disease (dialysis, renal transplant, or serum
creatinine 6 mg/dL)
Death (all-cause mortality)

Secondary outcome is time to a composite endpoint of fatal

or nonfatal cardiovascular events

Lewis EJ et al. N Engl J Med 2001;345:851-860.

Potential Pathogenic Properties

of Angiotensin II
Kidneys
Increased

intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow

Adapted from Opie and Gersh. Drugs for the Heart, 2001.

IRMA 2: Study Design

590 patients with hypertension, type 2 diabetes,
microalbuminuria,* and normal renal function
Double-blind treatment
Screening/enrollment

Control
Irbesartan 150 mg/d
Irbesartan 300 mg/d

3 weeks

Follow-up: 2 years

Control defined as placebo.

* Defined as albumin excretion rate 20-200 g/min.
Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)

IRMA 2: Clinical Outcome

Measures
Primary outcome:
Time

to occurrence of overt proteinuria

(UAER >200 mg/min)

Secondary outcomes:
Change

in UAER
Regression to normoalbuminuria
(UAER <20 mg/min)
Change in creatinine clearance
UAER, urinary albumin excretion rate.
Parving H-H et al. N Engl J Med. 2001;345:870-878.

IRMA 2: Mean Baseline

Characteristics
Irbesartan 150 mg/d

Irbesartan 300 mg/d

Control

195

194

201

Age (y)

58

57

58

Male (%)

66

71

69

BMI (kg/m2)

29.9

30.0

30.3

BP (mm Hg)

153/90

153/91

153/90

SeCr (mg/dL)

1.0

1.1

1.0

UAER (g/min)

58

53

55

HbA1c (%)

7.3

7.1

7.1

Duration of diabetes (y)

9.5

9.2

10.4

Control defined as placebo.

BMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbA 1c, glycosylated
hemoglobin.

IRMA 2 Primary End Point:

Time to Overt Proteinuria
20

Control (n=201)*
Irbesartan 150 mg/d (n=195)*
Irbesartan 300 mg/d (n=194)*

Patients (%)

15

RRR=39%
P=.08

10

RRR=70%
P<.001

0
0

12
Follow-up (mo)

18

22

24

RRR, relative risk reduction.

Control defined as placebo.
* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)

IRMA 2: Normalization* of UAER

45

P=.006

40

34

Patients (%)

35
30
25

21

24

20
15
10
5
0

Control
(n=201)

UAER, urinary albumin excretion rate.

Control defined as placebo.
* Normoalbuminuria defined as UAER of <20 mg/min.

150 mg/d
(n=195)

300 mg/d
(n=194)
Irbesartan

IRMA 2: Adverse Events

No. of Adverse Events (%)
Control group*
(n=201)

Irbesartan

Irbesartan

150 mg* (n=195)

300 mg* (n=194)

Cardiovascular events

18 (8.7)1

14 (6.9)2

9 (4.5)1

Serious AE

47 (22.8)1

32 (15.8)2

30 (15.0)2

18 (8.9)2

11 (5.5)2

Discontinuations due to AE 19 (9.2)2

Control defined as placebo.

Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)
could be added to all groups to help achieve target BP levels.
1. Parving H-H, et al. N Engl J Med. 2001;345:870-878.
2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.
*

IRMA 2: Summary
The renal benefits of irbesartan are independent of its
BP-lowering effects1
70%

risk reduction in the progression from microalbuminuria

to overt diabetic nephropathy
with irbesartan 300 mg/d vs control (P<.001) 1
More frequent restoration of normoalbuminuria with
irbesartan 300 mg/d vs control (P=.006)1

Irbesartan is safe & well tolerated2

Fewer

nonfatal CV events, serious AEs, and

due to AEs in the irbesartan groups 2
AE, adversediscontinuations
event.

1. Parving H-H et al. N Engl J Med. 2001;345:870-878.

2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.

IDNT: Study Design

1,715 patients with hypertension, type 2 diabetes, &
proteinuria 900 mg/d
Double-blind treatment
Screening/enrollment

Irbesartan*
Control*
Amlodipine*

Up to 5 weeks

Minimum follow-up:
approximately 2 years
(average follow-up, 2.6 years)

Control defined as placebo.

* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to
help achieve target BP.

IDNT: Clinical Outcome Measures

Primary outcome: time to composite end point
of
Doubling

of baseline SeCr
ESRD (dialysis, renal transplant, or SeCr 6 mg/dL)
Death (all-cause mortality)

Secondary outcome: time to composite end

point of
fatal

or nonfatal CV events

SeCr, serum creatinine; ESRD, end-stage renal disease.

Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IDNT: Mean Baseline Demographics

Irbesartan

Amlodipine

Control

579

567

569

Age (y)

59

59

58

Male (%)

65

63

71

Non-white (%)

24

31

28

31.0

30.9

30.5

History of CV disease (%)

27

30

29

Retinopathy (%)

69

64

67

Duration of diabetes (y)

15

14

15

BMI (kg/m2)

Control defined as placebo.

BMI, body mass index.
Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IDNT: Baseline Exam &

Laboratory Characteristics
Irbesartan

Amlodipine

Control

SBP (mm Hg)*

160

159

158

DBP (mm Hg)*

87

87

SeCr (mg/dL)*

1.67

1.65

1.69

Urine protein (g/24 h)

2.9

2.9

2.9

HbA1c (%)*

8.1

8.2

8.2

Control defined as placebo.

SeCr, serum creatinine; HbA1c, glycosylated hemoglobin.
* Mean.

87

IDNT Primary End Point:

Time to Doubling of SeCr, ESRD, or
Death
70
Irbesartan (n=579)
60
Amlodipine (n=565)

Patients (%)

50

Control (n=568)

40

RRR=23%
P=.006
P=NS

RRR=20%
P=.02

30
20
10
0
0

12

18

24
30
36
Follow-up (mo)

42

Control defined as placebo.

SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction.
Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

48

54

IDNT: Time to Doubling of SeCr

70
Irbesartan (n=579)
60
Amlodipine (n=567)

Patients (%)

50

RRR=37%
P<.001
RRR=33%
P=.003
P=NS

Control (n=569)

40
30
20
10
0
0

12

18

24
30
36
Follow-up (mo)

Control defined as placebo.

SeCr, serum creatinine; RRR, relative risk reduction.
Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

42

48

54

IDNT Secondary End Point:

CV Events*
30

Patients (%)

25

25.3

23.8

22.6

20
15
10
5
0

Control
(n=569)

Irbesartan
(n=579)

Amlodipine
(n=567)

No significant differences between groups.

Control defined as placebo.
* Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in

IDNT: Adverse Events

No. of AEs
Irbesartan

Amlodipine

Control

Early SeCr rise (n)2

Discontinuations due
to hyperkalemia [n (%)]1

11 (1.9)

3 (0.5)

2 (0.4)

Stopped study medicine [n (%)]2

134 (23)

133 (23)

140 (25)

SAEs/1000 days on drug (%)2

2.0

2.5

2.3

AE, adverse event; SAE, serious adverse event.

Control defined as placebo.
1. Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IDNT: Summary
Irbesartan reduced the composite risk of progression of renal
disease or total mortality, independent of its BP-lowering
effects
20%

RRR vs control (P=.02)

23% RRR vs amlodipine (P=.006)
No significant differences among groups for CV outcomes
Size

and duration of study was insufficient to detect any

differences
Irbesartan was generally safe and well tolerated
Lower

rate of SAEs in the irbesartan group

SAE, serious adverse event; RRR, relative risk reduction.

Lewis EJ et al. N Engl J Med. 2001;345:851-860.