Angiotensin Receptor Blockade: Applications to Clincal Care Timothy A. Denton, M.D. Divisions of Cardiology and Cardiothoracic Surgery Cedars-Sinai Medical.

Angiotensin Receptor Blockade:

Applications to Clincal Care

Timothy A. Denton, M.D.Divisions of Cardiology and

Cardiothoracic SurgeryCedars-Sinai Medical Center

Los Angeles

Outline

• JNC VI• “Undertreatment”• Physiology• HTN drugs• ARB’s

JNC VI

JNC VI

Joint National Committee onPrevention, Detection, Evaluation,

and Treatment ofHigh Blood Pressure

JNC VI -- Arch Int Med 1997;157:2413

Why do we need blood pressure?

Why do we need blood pressure?

• Get blood to the scalp• Distribute flow quickly

Category Systolic Diastolic

Optimal <120 <80

Normal <130 <85

High-normal 130-139 85-89

Hypertension

Stage I 140-159 90-99

Stage II 160-179 100-109

Stage III >180 >110

Classification of HTN

JNC VI -- Arch Int Med 157:2413, 1997

Category Risk factors Target OrganDamage

CV Disease

Group A 0 0 0

Group B >1 (not DM) 0 0

Group C >1 or DM + +

Risk Classification

JNC VI -- Arch Int Med 157:2413, 1997

Category Group A Group B Group C

High-normal Lifestyle Lifestyle Drugs

Stage I Lifestyle Lifestyle (6 mo) Drugs

Stages II, III Drugs Drugs Drugs

Approach to HTN Therapy

JNC VI -- Arch Int Med 157:2413, 1997

Etiology of HTN

•RenalChronic pyelonephritisGlomerulonephritisPolycystic kidneyRenovascularOther renal

•EndocrineOral contraceptivesAdrenocortical (Cushing, hyperaldo,

17 hydroxylase, 11-hydroxylase)PheochromocytomaMyxedemaAcromegaly

Normal Pulse Pressure•Neurogenic

PsychogenicFamilial dysautonomiaPolyneuritisIncreased intracranial pressureSpinal cord section

•MiscCoarctationIntravascular volumePolyarteritis nodosaHypercalcemiaAcute intermittent porphyriaPre-eclampsia

Etiology of HTN

•Decreased aortic compliance•Increased stroke volume

AIThyrotoxicosisHyperkinetic heart syndromeFeverAV fistula / PDA

Wide Pulse Pressure

Physiology of HTN

Primary Hypertension•? central/peripheral adrenergic•? renal•? hormonal•? vascular

Physiology of HTN

Secondary• Wide Pulse Pressure

Aortic complianceStroke volume

•Normal Pulse PressureRenalEndocrineNeurogenicMisc

Epidemiology of HTNDiagnosis % Population

PrimaryRenal Parenchymal RenovascularEndocrine Primary aldo Cushing’s Pheo Oral contraceptiveMisc

92-94

2-31-2

0.3<0.1<0.12-40.2

Harrison’s Principles of Internal Medicine, 12th Edition

Classes of Anti-Hypertensives(1999 PDR)

Adrenergic blockersAlpha/Beta adrenergic blockersACE inhibitorsACE + Ca blockersACE + diureticsARB’sARB’s with diureticsBeta blockersBeta blockers with diureticsCalcium blockersDiureticsRauwolfia derivativesVasodilators

Preparations of Anti-Hypertensives by Class(1999 PDR)

Adrenergic blockersAlpha/Beta adrenergic blockersACE inhibitorsACE + Ca blockersACE + diureticsARB’sARB’s with diureticsBeta blockersBeta blockers with diureticsCalcium blockersDiureticsRauwolfia derivativesVasodilators

65

114542

156

25242

18

Total = 127

Special Considerations

In African-Americans: -- low probability of success with Beta blockers or ACE

or ARB’s

-- higher probability of success with diuretics or Ca blockers

Compelling Indications

Condition RecommendedTherapy

DM (type 1) + proteinuria ACE

CHF (low EF) ACE, diuretics

Sys HTN diuretics, Ca blockers

MI beta blockers, ACE

JNC VI -- Arch Int Med 157:2413, 1997

“The committee recognizes thatthe responsible clinician’sjudgment of the individual

patient’s needs remains paramount.”

JNC VI -- Arch Int Med 1997;157:2413

Undertreatment

National Data on HTN

51

73

31

55

10

29

0

10

20

30

40

50

60

70

80

90

100

NHANES II NHANES III

National Health and Nutrition Examination SurveyII - 1976-1989, III - 1988-1991

Per

cen

t Aware HTN

Rx HTN

HTN Goal

Undertreatment of Hypertension

Percentage of Patients withBP > 160/90

46.339.4

0102030405060708090

100

Index 2 years

Office Visit

Pe

rce

nt

Berlowitz, NEJM 1998;339:1957

Undertreatment of Hypertension

Percentage of Patients with BP "controlled"

60.6

25

0102030405060708090

100

<160/90 <140/90

Threshold for "control"

Pe

rce

nt

Berlowitz, NEJM 1998;339:1957

Undertreatment of Hypertension

Increases in HTN Therapy

35

3.2

0102030405060708090

100

DBP>90 <90, <165

BP Findings

Pe

rce

nt

Berlowitz, NEJM 1998;339:1957

If you have not achieved goal,

you must change your therapy

You push a medication’s doseto EFFECT

or SIDE EFFECTor maximal recommended dose

Drug Suboptimal Optimal

losartan 50 mg qd 100 mg qd

metoprolol 50 mg qd 0 mg qd

HCTZ 12.5 mg qd 0 mg qd

Patient Example

Combination Drugs:A Different Animal

• Beta blocker + diuretic• ACE + diuretic• ACE + calcium blocker• ARB + diuretic• Diuretic + diuretic• “other” + diuretic

Pressure/Volume Relation

Pressure = 150 mmHg

FluidFlux

Pressure = 120 mmHg

FluidFlux

Vasculature

Physiology

Goodfriend TL, New Engl J Med 1996 334(25):1649-54

Goodfriend TL, New Engl J Med 1996 334(25):1649-54

Angiotensinogen

Angiotensin I

Angiotensin II

ReninInhibitor

ACEInhibitor

AT1 receptorInhibitor

Renin

ACE

Endothelin-1

Vasopressin

Vaso-constriction

Vaso-dilatation

Adapted, Bonn, D. Lancet 1998;352:378

non-ACEalternativepathways(chymase,

cathepsin G,chymostatin

ATII generation)

Bradykinin

Inactiveproducts

ACE

? angioedema

cough

increase nitric oxide,prostacyclin

(improved endothelial function ?anti-atherosclerotic?)

hypotension

Hypothesized Atherosclerotic Effects Hypothesized Atherosclerotic Effects of Angiotensin IIof Angiotensin II

Causes SMC growth and migrationCauses SMC growth and migration Activates macrophagesActivates macrophages Increases platelet aggregationIncreases platelet aggregation Stimulation of PAI1Stimulation of PAI1 Made directly by SMCs & macrophagesMade directly by SMCs & macrophages A-II stimulation causes endothelial dysfunctionA-II stimulation causes endothelial dysfunction

Gibbons, G.H. et al, NEJM, 330(20):1431-1438.

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

Angiotensin II ReceptorsAngiotensin II Receptors

Angiotensin II FormationAngiotensin II FormationAlternate Pathways*Alternate Pathways*

• CAGECAGE• Cathepsin GCathepsin G• ChymaseChymase

ReninReninReninRenin

• t-PAt-PA• Cathepsin GCathepsin G• ToninTonin

ACEACEACEACE

Dzau, V.J. et al, J of Hypertension, 11(suppl 3):1993.

* The clinical significance ofthe alternate pathway is

unknown

AT Receptors

AT1 AT2

FetusVasculature

HeartVasculatureBrainAdrenal

Proposed Pathophysiologic Effects Proposed Pathophysiologic Effects of Angiotensin IIof Angiotensin II

Hypertension, 23(2):258, 1994.

Angiotensin IIAngiotensin II

ATAT11

ReceptorReceptorVasoconstrictionVasoconstrictionAldosteroneAldosteroneProductionProduction

Cell GrowthCell Growth

LVHLVHVascularVascular

RemodelingRemodeling

TVRTVR

BPBP

Sodium/WaterSodium/WaterRetentionRetention

BPBP

AT Receptors

AT1 AT2

anti-proliferationHypertrophyProliferationThirstAldosteroneProliferation

AT ReceptorsAT Receptors

AT1 AT2

decreaseddecreasedProliferationProliferation

ATII

losartanlosartan

1000x

ARB’s

Angiotensin Receptor Blockers

Angiotensin II ReceptorBlocking Agents

Generic Trade Date Publications(1995-1999)

losartan Cozaar 12/95 1,296valsartan Diovan 12/96 117irbesartan Avapro 9/97 96

candesartan Atacand 6/98 154eprosartan Teveten 1/5/98 48tasosartan Verdia 1/28/98 6telmisartan Micardis 11/12/98 23

1/6/2000

Angiotensin II ReceptorBlocking Agents

Generic Trade Peak ½ Life DoseSchedule

Dose

losartan Cozaar 1-4 hrs 2-10 hrs qd or q12h 25-100 mg

valsartan Diovan 2-4 hrs 6 hrs qd 80-320 mg

irbesartan Avapro 1.5-2 hrs 11-15 hrs qd 150-300 mg

candesartan Atacand 3-4 hrs 9 hrs qd or q12h 8-32 mg

eprosartan Teveten 1-2 hrs variable Q12h 400-600 mg

tasosartan Verdia 1-2 hrs 10 hrs Q24h 100 mg

telmisartan Micardis 0.5-1 24 Q24h 40-160 mg

ELITE

Bertram, Lancet 1997;349:747

• Evaluation of Losartan In The Elderly• Losartan vs captopril• Primary endpoint

Increase of creat >0.3 mg%• Secondary endpoints

All cause mortalityHospital admit for CHFDeath + admit for CHF

ELITE

Bertram, Lancet 1997;349:747

• Age > 65 years• CHF NYHA class II-IV• EF < 40%• No prior ACE therapy• Double-blind, randomized, placebo• losartan-352 pts, captopril-370 pts• 48 weeks of follow-up

ELITE

Bertram, Lancet 1997;349:747

Persistent Increased Creatinine

10.5 10.5

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

ELITE

Bertram, Lancet 1997;349:747

Single Rises in Creatinine

26.1 29.7

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

P=0.42

ELITE

Bertram, Lancet 1997;349:747

Death and/or CHF Admissions

9.4 13.2

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

P=0.075

ELITE

Bertram, Lancet 1997;349:747

All Cause Mortality *

4.8 8.7

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

P=0.035

*primarily SCD

ELITE

Bertram, Lancet 1997;349:747

NYHA Class I or II

66 64

80 81

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

P=0.035

ELITE

Bertram, Lancet 1997;349:747

DC'ed Rx or Died

18.530

0102030405060708090

100

Losartan Captopril

Pe

rce

nt

P<0.001

ELITE II

Unpublished

• Evaluation of Losartan In The Elderly II• Losartan vs captopril• Primary endpoint

All cause mortality

ELITE II

Unpublished

• Age 62.7 + 11 years• 80% male• NYHA Class II / III / IV -- 61.7 / 36.2 / 1.9%• LVEF 26.7 + 7.1%• Double-blind, randomized, placebo• Total 3,152 patients• Follow-up until 510 deaths

ELITE II

Unpublished

All Cause Mortality

15.9 14.9

0102030405060708090

100

Losartan Captopril

Perc

en

t p = 0.16

ELITE II

Unpublished

Sudden Cardiac Death

9 7.3

0102030405060708090

100

Losartan Captopril

Perc

en

t p = 0.08

AT1 Inhibitors

“Indeed the incidence of all side effects of AT1 receptor antagonist appears to be much the same as placebo, which cannot be said for any other class of antihypertensive drug.”

Struthers, Heart 1998;80:5

AT Effects on Coagulation

Chabielska, J Physiol Pharm 1998;49:251

7 day Rxcaptopril

7 day Rxlosartan

control

Rats

Abdominal Aortic Loop Thrombosis

Thrombosis 46% lessThrombosis

42% lessThrombosis

Tedesco, J Hum Hypertens 1998;12:505

Reduction in LV Mass

-11

-5

-20

-15

-10

-5

0

Losartan HCTZ

LV

ma

ss

re

du

c -

g/m2 P=0.38

Special Considerations

• Losartan is a uricosuric

ARB’s

• Very similar to ACE inhibitors• VERY well tolerated, ?placebo rate of side effects• Advantageous in ACE cough• Advantageous in ACE angioedema• May have other, advantageous effects

(thrombosis, proliferation, renal)• Consider as primary therapy in selected subsets

Summary• Please, find more hypertensive patients

• Please, treat more hypertensive patients

• Please, achieve goal in more hypertensive patients

• Consider the underlying pathology

• Consider a broad range of old and new drugs