hypertension overview clinical trials and management

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

10 20 30 40 50 60

High BP

CAD

CHF

Stroke

Other

50,000,000

12,200,000

4,600,000

4,400,000

2,800,000

Prevalence (millions)

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

•Estimated Number of Persons With Cardiovascular Disease in the US

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

(24%)

Age Distribution of Hypertensives in US Population

(NHANES III and the 1991 Census)

3.7

9.5

13

21.3

23.7

19.2

9.6

0

5

10

15

20

25

30

18-29 30-39 40-49 50-59 60-69 70-79 80+

Hyp

ert

en

siv

es W

ith

in A

ge

Gro

up

(%

)

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

Age Groups (y)

47.4 million 47.4 million hypertensiveshypertensives

26.0% of US 26.0% of US populationpopulation

26% 74%

<40 40-49 50-59 60-69 70-79 80+Age (y)

17% 16% 16% 20% 20% 11%

Distribution of Hypertension Subtype in the untreated Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III by AgeHypertensive 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)

0

20

40

60

80

100

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

Frequency of hypertension

subtypes in all untreated

hypertensives (%)

Peripheral vascular disease

Morbidity

Disability

Renal disease

CADCHFLVHStroke

Hypertension

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

Hypertension: A Significant CV and Renal Disease Risk Factor

Benefits of Lowering BP

Average Percent Reduction

Stroke incidence 35–40%

Myocardial infarction 20–25%

Heart failure 50%

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

19

37

31

56

21

11

39

21

0

10

20

30

40

50

60

PA

R%

/ N

NT

Men PAR% Women PAR% Men NNT Women NNT

Treatment to <140/90 mmHg Treatment to <120/80 mmHg

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 RatesTrends in awareness, treatment, and control of high

blood pressure in adults ages 18–74National Health and Nutrition Examination Survey, Percent

II

1976–80

II

(Phase 1)

1988–91

II

(Phase 2)

1991–94 1999–2000

Awareness 51 73 68 70

Treatment 31 55 54 59

Control 10 29 27 34

Sources: Unpublished data for 1999–2000 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

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program

Blood Pressure Classification

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension 140–159 or 90–99

Stage 2 Hypertension >160 or >100

BP Classification SBP mmHg DBP mmHg

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 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.

New Features and Key Messages

4-Year Progression To Hypertension: The Framingham Heart Study

5

18

37

0

10

20

30

40

50

Optimal Normal High-Normal

Pat

ien

ts (

%)

(<120/80 mm Hg) (130/85 mm Hg)(130-139/85-89 mm Hg)

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

Participants age 36 and older

HOT Study: Significant Benefit FromHOT Study: Significant Benefit FromIntensive Treatment in the Diabetic SubgroupIntensive Treatment in the Diabetic Subgroup

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

0

5

10

15

20

25

90 85 80

Major cardiovascular events/1,000 patient-years

p=0.005 for trend

mm Hg

Target Diastolic Blood Pressure

SBP-Associated Risks: MRFIT

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

SBP versus DBP in Risk of CHD Mortality

Diastolic BP(mm Hg)

Systolic BP(mm Hg)

CHD Death Rate

100+90–99

80–8975–79

70–74<70 <120

120–139

140–159

160+

48.3

20.6

10.311.8

8.88.5

9.2

23.8

16.9

13.912.8

12.611.8

31.0

25.524.6 25.3

25.224.9

37.434.7

43.8

38.1

80.6

Disease Relative Risk

Kidney failure (ESRD) 2.8

Stroke 2.7

Heart failure 1.5

Peripheral vascular disease 1.8

Myocardial infarction* =1.6

Coronary artery disease 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.

Elevated SBP Alone Is Associated With Increased Risk of Cardiovascular and

Renal Disease

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

*P=.0003 vs placebo.

Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.

Risk ReductionR

isk

Red

uct

ion

(%

)

0

–10

–20

–30

–40

–50

–36*

Total Mortality

–13

Stroke

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 160–219 mm Hg and DBP <95 mm Hg

Treatments: Nitrendipine (10–40 mg/day) with possible addition or substitution of:

– Enalapril (5–20 mg/day)

– Hydrochlorothiazide (12.5–25 mg/day)

Placebo

Follow-up: 2 years (median)

Endpoint: Total strokeMyocardial infarction

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

Syst-Eur: Outcomes

*P=.003; †P=.03; ‡P=.12; §P<.001.

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

Pe

rce

nt

Re

du

cti

on

0

–5

–10

–15

–20

–25

–30

–35

–40

–45 –42*

HeartFailureStroke

All CardiacEndpoints

All Fatal/NonfatalCardiac EndpointsMI

–26†

–29‡–30‡

–31§

Risk Reduction

Pulse Pressure

• 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.

PP = SBP – DBPPP = SBP – DBP

ATP III: The Metabolic Syndrome*

*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 ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

<40 mg/dL<50 mg/dL

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

110 mg/dLFasting glucose130/85 mm HgBlood pressure

HDL-C150 mg/dLTG

Abdominal obesity† (Waist circumference‡)

Defining LevelRisk Factor

© 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)

80.584.2

76.7

84.6

73.2

82.986.5

57.662.6

22.216.7

95.1

0

10

20

30

40

50

60

70

80

90

100

Men Women

Pe

rce

nt

(%)

of

Me

tab

oli

c S

yn

dro

me

Su

bje

cts

Waist Cir >40cm M/>35 cm W Blood Pressure >=130/85 or RxFasting Trig. >=150 mg/dl HDL-C <40 mg/dl M/<50 mg/dl WLDL-C >=130 mg/dl Fasting Glucose 110-125 mg/dl

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)

28.2

51.2 50.646.2

38.1

80.5 82.1

45.1

0

10

20

30

40

50

60

70

80

90

Men Women

Pro

po

rtio

n o

f C

HD

Ev

en

ts P

rev

en

ted

(P

AR

%)

BP only HDL-C only LDL-C only All 3 factors

***

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

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

ALLHAT

Years to CHD Event0 1 2 3 4 5 6 7

Cumulative CHD Event Rate

0

.04

.08

.12

.16

.2

Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209 Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215 Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

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

ALLHAT

ChlorthalidoneAmlodipineLisinopril

Cumulative Stroke Rate

Years to Stroke0 1 2 3 4 5 6 7

0

.02

.04

.06

.08

.1

Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567 Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

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

ALLHAT


Cumulative CHF Rate

Years to HF0 1 2 3 4 5 6 7

0

.03

.06

.09

.12

.15

Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group

HR (95% CI) p value

A/C 1.38 (1.25-1.52) <.001

L/C 1.19 (1.07-1.31) <.001

ALLHAT


Number at risk: Chlor 15,255 14,528 13,898 13,224 11,511 6,369 3,016 384 Amlo 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 Lisin 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313

Overall ConclusionsALLHAT

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 thiazide-type 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 physician’s 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 Brief Description

In-office Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm.

Ambulatory BP monitoring

Indicated for evaluation of “white-coat” HTN. Absence of 10–20% 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.

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. Arch Intern Med 1997;157:2413.

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

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 Approximate SBP reduction(range)

Weight reduction 5–20 mmHg/10 kg weight loss

Adopt DASH eating plan 8–14 mmHg

Dietary sodium reduction 2–8 mmHg

Physical activity 4–9 mmHg

Moderation of alcohol consumption

2–4 mmHg

For Prevention and Management

Lifestyle Modifications

• Lose weight if overweight

• Limit alcohol intake

• Increase aerobic physical activity

• Reduce sodium intake

• Maintain adequate intake of potassium

• Maintain adequate intake of calcium and magnesium

• Stop smoking

• Reduce dietary saturated fat and cholesterol

For Overall and Cardiovascular Health

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

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg)

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

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Classification and Management of BP for adults

BP classificatio

n

SBP* mmHg

DBP* mmHg

Lifestyle modificati

on

Initial drug therapy

Without compelling indication

With compelling indications

Normal <120 & <80 Encourage

Prehypertension

120–139

or 80–89

Yes No antihypertensive drug indicated.

Drug(s) for compelling indications. ‡

Stage 1 Hypertension

140–159

or 90–99

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

Drug(s) for the compelling indications.‡

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

Stage 2 Hypertension

>160 or >100 Yes Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB).

*Treatment determined by highest BP category.†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.

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 1–2 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 Clinical Trial BasisACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

THIAZ, BB, ACEI, ARB, ALDO ANT

BB, ACEI, ALDO ANT

THIAZ, BB, ACE, CCB

Heart failure

Postmyocardialinfarction

High CAD risk

Diabetes

Chronic kidney disease

Recurrent stroke prevention

Compelling Indications for Individual Drug Classes

Compelling Indication Initial Therapy Options

Clinical Trial Basis

NKF-ADA Guideline, UKPDS, ALLHAT

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

PROGRESS

THIAZ, BB, ACE, ARB,

CCB

ACEI, ARB

THIAZ, ACEI

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.

CCBs, calcium channel 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.

Stroke 456 529 0.87 (0.77-0.98)CHD 567 510 1.12 (1.00-1.26)Heart Failure 278 250 1.12 (0.95-1.33)Major CV Events 1,251 1,234 1.02 (0.95-1.10)CV Death 425 405 1.05 (0.92-1.20)Total Mortality 776 776 1.01 (0.92-1.11)

Relative RiskFavors CCBs Favors diuretics or beta blockers

CCBs(n=11,685)

Diuretics or Beta Blockers

(n=11,769)

0.5 1.0 2.0

No. of Events*

Relative Risk(95% CI)

Relative Risk of CV Events and Mortality:CCBs vs Diuretics or Beta Blockers

-22(P<.001)

MI, Stroke,CV Death(primary

end point)

-26(P<.001)

CV Death

-20(P<.001)

MI

-32(P<.001)

Stroke

-16(P=.005)

All-causeDeath

-35

-30

-25

-20

-15

-10

-5

0

Ris

k R

educ

tion

(%)

HOPE: Risk Reduction of CV EventsAssociated with ACEI (RAS Inhibition) Treatment

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.

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.

Stroke 425 402 1.05 (0.92-1.19)CHD 423 420 1.00 (0.88-1.14)Heart Failure 223 250 0.92 (0.77-1.09)Major CV Events 1,018 1,004 1.00 (0.93-1.08)CV Death 350 348 1.00 (0.87-1.15)Total Mortality 639 618 1.03 (0.93-1.14)

Relative RiskFavors ACE inhibitors Favors diuretics or beta blockers

No. of Events*

ACE Inhibitors(n=8,097)

Diuretics or Beta Blockers

(n=8,064)

0.5 1.0 2.0

Relative Risk(95% CI)

Relative Risk of CV Events and Mortality:ACE Inhibitors vs Diuretics or Beta Blockers

Reversal of LV Hypertrophy By Antihypertensive Treatment

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

Ch

ang

e in

LV

mas

s in

dex

(%)

0

-5

-10

-15

-20

-25

Diuretics -blockers

Calciumchannelblockers

ACEinhibitors

p<.01

p<.01

7%6%

9%

13%

Regression of LV HypertrophyPredicts Prognosis

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

Pro

bab

ility

of

even

t-fr

ee s

urv

ival

(%)

Rat

e o

f ev

ents

(p

er 1

00 p

atie

nt-

yrs)

Time to event (wk)

0 100 200 300 400 500

P=.002

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

100

90

80

70

0

60

50

7

6

5

4

1

3

2

0

Regressors (n=52)

Nonregressors (n=50)

Irbesartan and Atenolol in Hypertension and LVH

Study Design

Single-blindPlacebo

Irbesartan 150-300 mg

Atenolol50-100 mg

Addition of HCTZ12.5-25 mgif SeDBP

90 mm Hg

Addition of Felodipine5-10 mgif SeDBP

90 mm Hg

Wk: -4 0 12 2448

* BP, echocardiography, neurohormone measurements.

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

*

DoubleBlind

* * *

Irbesartan vs Atenolol in Hypertension and LVH: SeDBP Reduction

-20

-15

-10

-5

012 wk 24 wk 48 wk

% r

edu

ctio

n in

SeD

BP

Irbesartan Atenolol

*

*† * *

**

* p<.001 vs baseline.† p<.028 irbesartan vs atenolol.


Irbesartan vs Atenolol in Hypertension and LVH: LVMI Reduction

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

% c

han

ge

in L

VM

I (g

/m2 )

*p<.001 vs baseline; †p=.024 irbesartan vs atenolol.

12 wk

*

24 wk

*

*

48 wk

*

*

†


Irbesartan 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 Dahlöf B et al. Am J Hypertens. 1997;10:705-13.

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

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

LIFE: DosingTitration to target blood pressure: <140 / <90 mmHg

Placebo

Run-in

Losartan 50 mg

Atenolol 50 mg

Losartan 50 mg + HCTZ 12.5 mg

Losartan 100 mg + HCTZ 12.5 mg

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

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

LIFE: Blood Pressure Results – Follow-up

0 6 12 18 24 30 36 42 48 54Study Month

40

60

80

100

120

140

160

180

Systolic

Diastolic

Mean Arterialmm

Hg

AtenololLosartan

Atenolol 145.4 mmHg

Losartan 144.1 mmHg

Atenolol 80.9 mmHg

Losartan 81.3 mmHg

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

Losartan Atenolol (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

LIFE: Primary and Select Secondary Outcomes

Adjusted*

* 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 Dahlöf 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 sitewww.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 choiceType 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 MRFIT: Association of Systolic BP and Cardiovascular Death in Type 2 DiabetesCardiovascular Death in Type 2 Diabetes

250

225

200

175

150

125

100

75

50

0

25

< 120 120–139 140–159 160–179 180–199 200

Systolic blood pressure (mm Hg)

Cardiovascular mortality

rate/10,000 person-yr

Nondiabetic

Diabetic

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

Veterans Administration Hypertension and Screening Clinics

15-Year ESRD Rates and Risk Ratios by BaselineSystolic Blood Pressure

SBP (mm Hg) Risk Ratio

< 140> 140 but < 151> 151 but < 165> 165 but < 180> 180

1.001.001.082.075.62

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 BaselineDiastolic Blood Pressure

DBP (mm Hg) Risk Ratio

< 94> 94 but < 100> 100 but < 106> 106 but < 118> 118

1.001.050.891.544.18

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 United Kingdom Prospective Diabetes Study (UKPDS): ResultsStudy (UKPDS): Results

• Tight blood pressure control* with captopril- or 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 NephropathyBurden 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 nephropathy2,3

Prevalence of nephropathy 57% after 25 years of type 2 diabetes4

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 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.University of Michigan; 1999. NIH Contract no. NO1-DK-3-2202.

2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72.2. American Diabetes Association. Diabetes Care. 2001;24 (supp 1):S69-72.3. Ritz E, et al. Am J Kidney Dis. 1996;27:167-194.3. Ritz E, et al. Am J Kidney Dis. 1996;27:167-194.4. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.4. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.5. Ruggenenti P et al. J Am Soc Nephrol. 1998;9:2336-2343.5. Ruggenenti P et al. J Am Soc Nephrol. 1998;9:2336-2343.

Diabetic NephropathyBurden 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;36:1113-1117.1. Koch M et al. Diabetologia. 1993;36:1113-1117.2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42. 2. Bakris GL. Diabetes Res Clin Pract. 1998;39:S35-S42. 3. Grundy SM et al. Circulation. 1999;100:1134-1146.3. Grundy SM et al. Circulation. 1999;100:1134-1146.

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

Correlation Between MAP & Renal Function

GF

R D

eclin

e(m

L/m

in/y

)

0

-2

-4

-6

-8

-10

-12

-14

MAP (mm Hg)

95 98 101 107104 110 113 116 119

r=0.69; P<.05

UntreatedHTN

130/85 140/90

Microalbuminuria as a Risk Factor for Death in Type 2 Diabetes

UAC, urinary albumin concentration.Adapted from Schmitz A et al. Diabetes Med. 1988;5:126-134.

Years after Diagnosis

Sur

viva

l

UAC 15 g/mL

UAC 16-40 g/mL

UAC 41-200 g/mL

0.0

0.4

1.0

0.8

0.6

0.2

0 5 1021 3 4 76 8 9 11

Proteinuria & Risk of CV Mortality,Stroke, & CHD Events in

Type 2 Diabetes

CHD, coronary heart disease; UPC, urinary protein concentration.CHD, coronary heart disease; UPC, urinary protein concentration.* Defined as CHD death or nonfatal MI.* Defined as CHD death or nonfatal MI. Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.Adapted from Miettinen H et al. Stroke. 1996;27:2033-2039.

A: UPC <150 mg/L B: UPC 150-300 mg/L C: UPC >300 mg/L

1.0

0.9

0.8

0.7

0.6

0.5

00 10 20 30 40 50 60 70 80 90 Stroke CHD Events*

P<.001 for trends

Inci

denc

e (%

)

Red

uctio

n in

Sur

viva

l due

to

CV

Mor

talit

y

Months

A

B

C

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

0

10

20

30

40

* Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or * Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or hypoglycemia.hypoglycemia.† † Fatal or nonfatal.Fatal or nonfatal.‡ ‡ Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure.Retinopathy requiring photocoagulation, vitreous hemorrhage and fatal or nonfatal renal failure. Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs Mean BP achieved with captopril- or atenolol-based therapy: 144/82 mm Hg (tight BP control) vs 154/87 mm Hg (less tight BP control).154/87 mm Hg (less tight BP control). Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.Adapted from UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

Risk Reduction of Diabetes-RelatedEnd Points with Tight BP Control

Ris

k R

edu

ctio

n (

%)

Diabetes-related Mortality* Stroke†

Microvascular End Points‡

Myocardial Infarction

0

10

20

30

40

50

32

44

37

21

HOT: Significant Benefit From Intensive Antihypertensive Treatment in Diabetes

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

0

5

10

15

20

25

90 85 80

Maj

or

CV

Eve

nts

*/10

00

Pat

ien

t-yr

s in

Hyp

erte

nsi

ve

Pat

ien

ts w

ith

Dia

bet

es

P=.005 for trend

Target DBP (mm Hg)

Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes

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

Pro

gre

ssio

n t

o D

eath

, Dia

lysi

s,P

rog

ress

ion

to

Dea

th, D

ialy

sis,

or

Tra

nsp

lan

t (%

)o

r T

ran

spla

nt

(%)

CaptoprilCaptopril

PlaceboPlacebo

Follow-up (y)Follow-up (y)

00 11 22 33 4400

1010

2020

3030

4040

**

SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure.SeSBP, seated systolic blood pressure; SeDBP, seated diastolic blood pressure. Control defined as placebo.Control defined as placebo.* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to to all groups to help achieve target BP levels.all groups to help achieve target BP levels. At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% At the end of 2-year follow-up, 56% of patients in the control group, 45% in the irbesartan 150-mg group, and 43% inin the irbesartan 300-mg group were receiving concomitant antihypertensive agents.the irbesartan 300-mg group were receiving concomitant antihypertensive agents. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.

IRMA 2: Blood Pressure Response

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

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

Mea

n S

eSB

P a

nd

SeD

BP

(mm

Hg

)

0 3 6 9 12 15 18 21 24 27Months

0

70

130

160

80

90

100

110120

140

150

14

18

16

12

10

8

6

4

2

0

Subjects(%)

Control (n=201)

150 mg(n=195)

300 mg(n=194)

Irbesartan

9.7

5.2

14.9

RRR=39%P=0.08

RRR=70%P<0.001

IRMA 2 Primary EndpointDevelopment of Overt Proteinuria

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

IDNT: Systolic BP, Mean Arterial Pressure, & Diastolic BP Response

Control defined as placebo.Control defined as placebo.Patients received an average of 3.0 concomitant antihypertensive agents in the irbesartan and amlodipine groups, 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.and 3.3 concomitant agents in the control group.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IrbesartanIrbesartanAmlodipineAmlodipineControlControl

00 66 1212 1818 2424 3030 3636 4242 4848 5454

Follow-up Visit (mo)Follow-up Visit (mo)

8080

100100

120120

140140

160160

SBPSBP

MAPMAP

DBPDBP

BP

(m

m H

g)

BP

(m

m H

g)

Subjects (%)

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

20

30

40

50

60

70

IDNT Primary Endpoint:Time to Doubling of Serum Creatinine, ESRD, or Death

Irbesartan

Amlodipine

Control

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

RRR 20%P=0.02

P=NS

RRR 23%P=0.006

IDNT & RENAAL: Study Design

SeCr, serum creatinine; ESRD, end-stage renal disease.SeCr, serum creatinine; ESRD, end-stage renal disease.† † Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.‡ ‡ Brenner BM et al. N Engl J Med. 2001;345:861-869.Brenner BM et al. N Engl J Med. 2001;345:861-869.

Patients:Patients: 1,715 HTN patients with type 2 1,715 HTN patients with type 2 1,513 HTN patients with 1,513 HTN patients with diabetes & nephropathydiabetes & nephropathy type 2 diabetes & type 2 diabetes & nephropathynephropathy

Treatment arms:Treatment arms: irbesartan, amlodipine,irbesartan, amlodipine, losartan, placebolosartan, placebo

placeboplacebo

Target BP:Target BP: 135/85 mm Hg135/85 mm Hg 140/90 mm Hg140/90 mm Hg

Adjunctive therapy:Adjunctive therapy: Permitted except ARBs, Permitted except ARBs, Permitted including Permitted including ACE ACE inhibitors, or CCBs inhibitors, or CCBs CCBs, except ARBs or CCBs, except ARBs or ACE inhibitorsACE inhibitors

Primary outcome:Primary outcome: Composite of doubling ofComposite of doubling of Composite of doubling of Composite of doubling of SeCr, SeCr, ESRD, or deathESRD, or death SeCr, ESRD, or deathSeCr, ESRD, or death

Secondary outcomes: Secondary outcomes: CV events CV events CV eventsCV events

Mean Follow-up:Mean Follow-up: 2.6 years2.6 years 3.4 years3.4 years

RENAALRENAAL‡‡IDNTIDNT††

IDNT and RENAAL Trial Results

Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006) -4 (P=0.69) ESRD, or death

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 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12 (P=0.29) & Mortality

Losartan vs control

Irbesartan vs control

Irbesartan vs amlodipine

Amlodipine vs control

RRR (%)

Comparison of Major Endpoints

RENAAL IDNT

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 OlderPersons

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 HTN—consider 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 drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)• Over-the-counter (OTC) drugs and herbal supplements

Excess alcohol intake Identifiable causes of HTN

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 population’s BP, thus potentially reducing morbidity, mortality, and the lifetime risk of an individual’s 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

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 Propertiesof Angiotensin II

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


Potential Pathogenic Propertiesof Angiotensin II (continued)

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 ofAntihypertensive 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 ImprovingAdherence 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 ImprovingAdherence 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.

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

Racial and Ethnic Groups

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.

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

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.

Antihypertensive Drugs Used in Pregnancy (continued)

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 FiveRandomized Trials of Antihypertensive

Treatment in the Elderly

Stroke0

100

200

300

400

500

600

78

288

T

T = TreatmentC = Control

= Fatal events

120

438

C

CHD

208

346

T279

438

C

Vascular deaths

To

tal

nu

mb

ers

of

ind

ivid

ua

ls a

ffec

ted

383

T

494

C

All other deaths

34% (6)2P <0.0001

% (SD) reductionin odds

19% (7)2P <0.05

23% (6)2P <0.001

–7% (8) 2P >0.5

344362

TC

SHEP STOP-HTN MRC SYST-EUR(1991) (Dahlöf, 1991) (1992) (1997)

Mean BP 170/77 195/102 185/91 174/85at entry (mm Hg)

Effects of Therapy in Elderly Hypertensive Patients

Double-blind Treatment

Up to 5 weeks

Screening/EnrollmentIrbesartan 150 mg*

Irbesartan 300 mg*

Follow-up: 2 years

Placebo/Control group*

IRMA 2: Study Design

• 590 patients with hypertension, type 2 diabetes, microalbuminuria (albumin excretion rate 20–200 µg/min), and normal renal function

* 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.


Mechanism of Action ofMechanism of Action ofAngiotensin II Receptor AntagonistsAngiotensin II Receptor Antagonists

Angiotensinogen

Angiotensin I

Angiotensin II

AT2 receptor AT1 receptor Other ATreceptors

Bradykinin

Inactive

peptides

VasodilationAttenuate growth anddisease progression

ACEinhibitors

Alternatepathways

AIIRAs

?

?

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


IDNT: Study Design

• 1,715 patients with hypertension, type 2 diabetes, and proteinuria 900 mg/day

Double-blind Treatment

Up to 5 weeks

Screening/EnrollmentPlacebo/Control group*

Amlodipine*

Minimum follow-up: approximately 2 years

(average follow-up 2.6 years)

Irbesartan*

* 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.


IDNTClinical 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


KidneysKidneys Increased intraglomerular pressureIncreased intraglomerular pressure Increased protein leakIncreased protein leakGlomerular growth and fibrosisGlomerular growth and fibrosis Increased sodium reabsorptionIncreased sodium reabsorptionDecreased renal blood flowDecreased renal blood flow


Potential Pathogenic Propertiesof Angiotensin II

Double-blind treatment

3 weeks

Screening/enrollment

Irbesartan 150 mg/d†

Irbesartan 300 mg/d†

Follow-up: 2 years

Control†

IRMA 2: Study Design 590 patients with hypertension, type 2 diabetes,

microalbuminuria,* and normal renal function

Control defined as placebo.Control defined as placebo.* Defined as albumin excretion rate 20-200 µg/min.* Defined as albumin excretion rate 20-200 µg/min.† † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.

IRMA 2: Clinical Outcome Measures

Primary outcome:Time to occurrence of overt proteinuria

(UAER >200 mg/min)

Secondary outcomes:Change in UAERRegression to normoalbuminuria

(UAER <20 mg/min)Change in creatinine clearance

UAER, urinary albumin excretion rate.UAER, urinary albumin excretion rate.Parving H-H et al. N Engl J Med. 2001;345:870-878.Parving H-H et al. N Engl J Med. 2001;345:870-878.

N

Age (y)

Male (%)

BMI (kg/m2)

BP (mm Hg)

HbA1c (%)

SeCr (mg/dL)

Irbesartan 150 mg/d

195

58

66

29.9

153/90

7.3

1.0

Irbesartan 300 mg/d

194

57

71

30.0

153/91

7.1

1.1

Control

201

58

69

30.3

153/90

7.1

1.0

IRMA 2: Mean Baseline Characteristics

UAER (µg/min) 58 53 55

Duration of diabetes (y) 9.5 9.2 10.4

Control defined as placebo.Control defined as placebo.BMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbABMI, body mass index; SeCr, serum creatinine; UAER, urinary albumin excretion rate; HbA 1c1c, glycosylated , glycosylated hemoglobin.hemoglobin.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.

IRMA 2 Primary End Point:Time to Overt Proteinuria

RRR, relative risk reduction. RRR, relative risk reduction. Control defined as placebo. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)* Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.Adapted from Parving H-H et al. N Engl J Med. 2001;345:870-878.

00 33 66 1212 1818 2222 2424

00

55

1010

1515

2020

Follow-up (mo)Follow-up (mo)

Control (n=201)*Control (n=201)*

Irbesartan 150 mg/d (n=195)*Irbesartan 150 mg/d (n=195)*

Irbesartan 300 mg/d (n=194)*Irbesartan 300 mg/d (n=194)* RRR=39%RRR=39%PP=.08=.08

RRR=70%RRR=70%PP<.001<.001

Pat

ien

ts (

%)

Pat

ien

ts (

%)

IRMA 2: Normalization* of UAER

UAER, urinary albumin excretion rate.UAER, urinary albumin excretion rate. Control defined as placebo. Control defined as placebo. * Normoalbuminuria defined as UAER of <20 mg/min.* Normoalbuminuria defined as UAER of <20 mg/min.† † Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels. Parving H-H et al. N Engl J Med. 2001;345:870-878.Parving H-H et al. N Engl J Med. 2001;345:870-878.

35

45

40

30

25

20

15

10

5

0Control†

(n=201)150 mg/d†

(n=195)300 mg/d†

(n=194)

Irbesartan

24

34

21

P=.006

Pat

ient

s (%

)

IRMA 2: Adverse Events

Cardiovascular eventsCardiovascular events 18 (8.7)18 (8.7)11 14 (6.9)14 (6.9)22 9 (4.5)9 (4.5)11

Serious AESerious AE 47 (22.8)47 (22.8)11 32 (15.8)32 (15.8)22 30 (15.0)30 (15.0)22

Discontinuations due to AEDiscontinuations due to AE 19 (9.2)19 (9.2)22 18 (8.9)18 (8.9)22 11 (5.5)11 (5.5)22

Control group* Control group* (n=201)(n=201)

IrbesartanIrbesartan

150 mg* (n=195)150 mg* (n=195)


300 mg* (n=194)300 mg* (n=194)

No. of Adverse Events (%)No. of Adverse Events (%)

Control defined as placebo. Control defined as placebo. * * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs)Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels.could be added to all groups to help achieve target BP levels.1. Parving H-H, et al. 1. Parving H-H, et al. N Engl J Med.N Engl J Med. 2001;345:870-878. 2001;345:870-878.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.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

discontinuations due to AEs in the irbesartan groups2 AE, adverse event.AE, adverse event.1. Parving H-H et al. N Engl J Med. 2001;345:870-878.1. Parving H-H et al. N Engl J Med. 2001;345:870-878.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.

IDNT: Study Design1,715 patients with hypertension, type 2 diabetes, & 1,715 patients with hypertension, type 2 diabetes, &

proteinuria proteinuria 900 mg/d900 mg/d

Double-blind treatmentDouble-blind treatment

Up to 5 weeksUp to 5 weeks

Screening/enrollmentScreening/enrollment

Control*Control*

Amlodipine*Amlodipine*

Minimum follow-up: Minimum follow-up: approximately 2 years approximately 2 years

(average follow-up, 2.6 years)(average follow-up, 2.6 years)

Irbesartan*Irbesartan*

Control defined as placebo. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and CCBs) could be added to all groups to help achieve target BP.help achieve target BP. Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IDNT: Clinical Outcome Measures

Primary outcome: time to composite end point ofDoubling of baseline SeCrESRD (dialysis, renal transplant, or SeCr ³6 mg/dL)Death (all-cause mortality)

Secondary outcome: time to composite end

point offatal or nonfatal CV events

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

NN

Age (y)Age (y)

Male (%)Male (%)

Non-white (%)Non-white (%)

BMI (kg/mBMI (kg/m22))

History of CV disease (%)History of CV disease (%)

Retinopathy (%)Retinopathy (%)


579579

5959

6565

2424

31.0 31.0

2727

6969

AmlodipineAmlodipine

567567

59 59

6363

3131

30.9 30.9

3030

6464

ControlControl

569569

58 58

7171

2828

30.5 30.5

2929

6767

IDNT: Mean Baseline Demographics

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

Duration of diabetes (y)Duration of diabetes (y) 1515 1414 1515

IDNT: Baseline Exam & Laboratory Characteristics

IrbesartanIrbesartan AmlodipineAmlodipine

DBP (mm Hg)*DBP (mm Hg)* 87 87 8787 8787

SeCr (mg/dL)*SeCr (mg/dL)* 1.671.67 1.651.65 1.691.69

Urine protein (g/24 h)Urine protein (g/24 h)†† 2.92.9 2.92.9 2.92.9

HbAHbA1c1c (%)* (%)* 8.18.1 8.28.2 8.28.2

ControlControl

SBP (mm Hg)*SBP (mm Hg)* 160 160 159159 158158

Control defined as placebo.Control defined as placebo. SeCr, serum creatinine; HbASeCr, serum creatinine; HbA1c1c, glycosylated hemoglobin., glycosylated hemoglobin.* Mean.* Mean.† † Median.Median. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

IDNT Primary End Point:Time to Doubling of SeCr, ESRD, or

Death

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

Irbesartan (n=579)Irbesartan (n=579)

Amlodipine (n=565)Amlodipine (n=565)

Control (n=568)Control (n=568)

RRR=20%RRR=20%PP=.02=.02

PP=NS=NS

RRR=23%RRR=23%PP=.006=.006

00 66 1212 1818 2424 3030 3636 4242 4848 5454


00

1010

2020

3030

4040

5050

6060

7070

Pat

ien

ts (

%)

Pat

ien

ts (

%)

IDNT: Time to Doubling of SeCr

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

Pat

ien

ts (

%)

Pat

ien

ts (

%)


00 66 1212 1818 2424 3030 3636 4242 4848 5454

00

1010

2020

3030

4040

5050

6060

7070Irbesartan (n=579)Irbesartan (n=579)

Amlodipine (n=567)Amlodipine (n=567)

Control (n=569)Control (n=569)

RRR=33%RRR=33%PP=.003=.003

PP=NS=NS

RRR=37%RRR=37%PP<.001<.001

IDNT Secondary End Point:IDNT Secondary End Point:CV EventsCV Events**

No significant differences between groups.No significant differences between groups. Control defined as placebo.Control defined as placebo.* Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in * Defined as death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in hospitalization,hospitalization, a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle.a permanent neurologic deficit caused by a cerebrovascular event, or lower limb amputation above the ankle. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

ControlControl(n=569)(n=569)

IrbesartanIrbesartan(n=579)(n=579)

AmlodipineAmlodipine(n=567)(n=567)

25.325.323.823.8

22.622.6

00

1010

2020

3030

55

1515

2525P

atie

nts

(%

)P

atie

nts

(%

)

Early SeCr rise (n)Early SeCr rise (n)22 00 00 11

Discontinuations dueDiscontinuations dueto hyperkalemia [n (%)]to hyperkalemia [n (%)]11 11 (1.9) 11 (1.9) 3 (0.5) 3 (0.5) 2 (0.4) 2 (0.4)

Stopped study medicine [n (%)]Stopped study medicine [n (%)]22 134 (23)134 (23) 133 (23)133 (23) 140 (25)140 (25)

SAEs/1000 days on drug (%)SAEs/1000 days on drug (%)22 2.02.0 2.52.5 2.32.3

IrbesartanIrbesartan AmlodipineAmlodipine ControlControl

No. of AEsNo. of AEs

AE, adverse event; SAE, serious adverse event.AE, adverse event; SAE, serious adverse event.Control defined as placebo.Control defined as placebo.1. Lewis EJ et al. N Engl J Med. 2001;345:851-860.1. Lewis EJ et al. N Engl J Med. 2001;345:851-860.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.2. Data on file, Bristol-Myers Squibb and Sanofi-Synthelabo, Inc.

IDNT: Adverse Events

IDNT: SummaryIrbesartan 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 groupSAE, serious adverse event; RRR, relative risk reduction.SAE, serious adverse event; RRR, relative risk reduction.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Lewis EJ et al. N Engl J Med. 2001;345:851-860.

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