use of the optimal dose of arbs in hypertension and cv diseases ass. prof. roland kassab head of...

Use of the optimal dose of ARBs in hypertension and CV diseases

Ass. Prof. Roland KASSABHead of Division of Cardiology

HDF, Beirut

12/02/2005

“The objective of antihypertensive therapy should be to not only lower the blood pressure but to prevent the lethal and disabling cardiovascular sequelae.”

Kannel WB. Eur Heart J. 1992;13(suppl G):34–42.

How to get it ?

• Achieve BP goals

• Select appropriate agents and dosages

• Take into account comorbidities

Blood Pressure Classification: JNC VII

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 HT 140–159 or 90–99

Stage 2 HT >160 or >100

BP Classification SBPmmHg DBPmmHg

Classification and Management of BP for adults

BP classification

SBP* mmHg

DBP* mmHg

Lifestyle modification

Initial drug therapy

Without compelling indication

With compelling indications

Normal <120 and <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.

US Guidelines 2003 (JNC VII)

Trial Publication Baseline BP Final BP

HOT Lancet 1998 175 / 105 142 / 83CAPPP Lancet 1999 161 / 99 150 / 90STOP-2 Lancet 1999 194 / 98 159 / 81ALLHAT JAMA 2000 145 / 83 136 / 76NORDIL Lancet 2000 173 / 106 151 / 88INSIGHT Lancet 2000 173 / 99 138 / 82LIFE Lancet 2002 174 / 98 145 / 81VALUE Am J Hypertens 2003 154 / 88 138 / 79

BP Levels in Clinical Trials

Adapted from S. Kjeldsen 2000 and updated April 2002.

VALUE: Number of Antihypertensive Medications Taken Before

Randomisation

NoneNone(7.2%)(7.2%)

1 1 MedicationMedication

(36.8%)(36.8%)

2 2 MedicationsMedications

(31.1%)(31.1%)

3 or More 3 or More MedicationsMedications

(24.9%)(24.9%)

VALUE: Analysis of Results Based on BP Control at 6 Months

Fatal/Non-fatal cardiac events

Fatal/Non-fatal stroke

All-cause death

Myocardial infarction

Heart failure hospitalisations

*SBP < 140 mmHg at 6 months.**P < 0.01.

Patients Treated With Valsartan Patients Treated With Amlodipine

Hazard Ratio 95% CI

0.4 0.6 0.8 1.0 1.2

Controlled patients*(n = 5253)

Non-controlled patients

(n = 2396)

**

**

**

**

0.4 0.6 0.8 1.0 1.2

Controlled patients*(n = 5502)

Non-controlled patients

(n = 2094)

Hazard Ratio 95% CI

**

**

**

**

0.76 (0.66–0.88)

0.60 (0.48–0.74)

0.79 (0.69–0.91)

0.83 (0.66–1.03)

0.62 (0.50–0.77)

Odds Ratio

0.73 (0.63–0.85)

0.50 (0.39–0.64)

0.79 (0.69–0.92)

0.91 (0.71–1.17)

0.64 (0.52–0.79)

Odds Ratio

Weber MA et al. Lancet. 2004;363:2047–49.

How to get it ?

• Achieve BP goals– difficult but feasible– multiple drugs needed

• Select appropriate agents and dosages


Natural History of CVD Natural History of CVD ProgressionProgressionElevated BP Target

Organ DamageMore Recent Paradigm

A Proposed Future Paradigm

Elevated BP Target Organ

Damage

Vascular Dysfunction

Elevated BP

Target Organ

Damage

Vascular Dysfunction

EndothelialDysfunction

Early Paradigm

Angina Pectoris

Stroke

MIRenal

Damage

LVH?

Hypertension: The Disease Continuum

The Cardiovascular Continuum:Targeting Mechanisms and

Mediators

Adapted from Dzau V et al. Am Heart J. 1991.

EndothelialDysfunction

Maladaptive Cardiovascular RemodelingMaladaptive Cardiovascular Remodeling

Target OrganDamage

Risk FactorsRisk FactorsRisk FactorsRisk Factors

Vascular Vascular DysfunctionDysfunction

Vascular Vascular DysfunctionDysfunction

Vascular Vascular DiseaseDiseaseVascular Vascular DiseaseDisease

Tissue Tissue InjuryInjury

(MI, Stroke) (MI, Stroke)

Tissue Tissue InjuryInjury

(MI, Stroke) (MI, Stroke)

PathologicaPathologicall

RemodelingRemodeling

PathologicaPathologicall

RemodelingRemodelingTarget Organ Target Organ DysfunctionDysfunction(CHF, Renal)(CHF, Renal)

Target Organ Target Organ DysfunctionDysfunction(CHF, Renal)(CHF, Renal)

End-stageEnd-stageOrgan FailureOrgan Failure

End-stageEnd-stageOrgan FailureOrgan Failure

DeathDeathDeathDeath

AngiotensinAngiotensinIIII

Angiotensin I

Angiotensinogen(Liver)

AT1 AT2

Angiotensin II

ACE inhibitor

ARBsAT1 receptor blocker

Renin inhibitor

Bradykinin

Peptides

Chymase

Local Ang II synthesis is independent of ACE

Several pathways of Ang II generation

de Gasparo et al. Pharmacol Rev 2000; 52:415

VasoconstrictionVascular proliferation Aldosterone secretionCardiac myocyte

proliferationIncreased sympathetic tone

VasodilationAntiproliferationApoptosis

AT1 AT2

Angiotensin II

Different roles of AT1 and AT2 receptors

de Gasparo et al. Pharmacol Rev 2000; 52:415

LV remodelling

TGF-PDGFbFGF

Fibroblast proliferation

Interstitial collagenMyocyte hypertrophy

TGF- = transforming growth factor beta; PDGF = platelet-derived growth factor; bFGF = basic fibroblast growth factor

Angiotensin II

Effects of Angiotensin II on Growth Factors/Cytokines and LV Remodeling

21

Vascular Health Benefits of RAAS blockers

• Positively impacts hypertension, oxidative stress, and endothelial functioning, thereby acting at the source of vascular damage

• Blocks the negative effects of Ang II at the AT1 receptor− improves vasodilation and arterial compliance

−reduces oxidative stress

− improves LVEF and LVIDD

−protects against end-organ damage

• Positively influences cardiovascular structure and function

Evidences from RCTs on the efficacy of RAAS blockers in preventing clinical events

along the CV continuum

• CV prevention in high risk patients– HOPE ACE-i ramipril

– EUROPA ACE-i perindopril

– PEACE ACE-i trandolapril

• High risk hypertensive patients– LIFE ARB losartan

– SCOPE ARB candesartan

– VALUE ARB=CCB valsartan/amlodipine

Evidences from RCTs on the efficacy of RAAS blockers in preventing clinical events

along the CV continuum

• Post-MI LVSD/HF– SAVE ACE-i captopril– AIRE ACE-i ramipril– TRACE ACE-i trandolapril– VALIANT ACE-i=ARB Valsartan/captopril

• Heart Failure– CONSENSUS ACE-i enalapril– SOLVD ACE-i enalapril– Val-HeFT ARB valsartan– CHARM ARB candesartan

Inhibiting Ang II Production and/or Its AT1 Receptor: Expanding Therapeutic Opportunities

• Hypertension

• Heart failure

• LV dysfunction/post-MI

• Prevention of ischemic cardiovascular events in high-risk patients

But what about dosages ?

0

100

0

100

0

100

Relationship Between Neurohormone Levels and Survival (CONSENSUS)

Ang II Norepinephrine Aldosterone

SurvivorsDeaths

Swedberg K et al. Circulation. 1990;82:1730-1736.

pg/mL pg/mL pg/mL

P<0.05P<0.05P<0.05P<0.05

P<0.05P<0.05P<0.05P<0.05

P<0.05P<0.05P<0.05P<0.05

0.50.5 1.01.0Odds Ratio

1.251.25

Favors captopril Favors losartan

All-cause mortality(15.9% vs 17.7%: P = 0.16)

Sudden death/resuscitated arrest(7.3% vs 9.0%: P = 0.08)

All-cause mortality/hospitalizations(44.9% vs 47.7%: P = 0.21)

Withdrawal rate 14.5% vs 9.4%: P <0.001

ELITE II: Summary of Major Findings

3,152 elderly CHF patients randomized to losartan (50 mg od) or captopril (50 mg tid)

Month 6 12 18 24 30 36

0

5

10

15

20

25

Eve

nt

Rat

e (%

)

Captopril 150 mg (n = 447 events)

Relative Risk = 1.13 (0.99–1.28); P = 0.069

0

OPTIMAAL:All-Cause Mortality

Losartan 50mg (n = 499 events)

Losartan 2744 2504 2432 2390 2344 2301 1285Captopril 2733 2534 2463 2423 2374 2329 1309

LIFE Trial in Hypertensive Patients With LVH on EKG

• Primary end point† 11% 13% 0.021• CV death 4% 5% 0.21• Stroke 5% 7% 0.001• MI 4% 4% 0.49• Total deaths 8% 9% 0.13

Losartan*(n = 4605)

Atenolol(n = 4588)

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

P

* Up to 100 mg†CV death, stroke or MI

Valsartan + ACE-I in HF: Valsartan Heart Failure Trial (Val-HeFT)

5010 patients 18 years; EF <40%; NYHA II–IV; LVIDd >2.9 cm/m2

ACE inhibitors (93%), diuretics (86%),digoxin (67%), β-blockers (36%)

Valsartan 40 mg bid titrated to 160 mg bid

906 deaths (events recorded)

Randomized to

Receiving standard therapy

Placebo

EJ = ejection fraction; LVIDd = left ventricular internal diastolic diameter.Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.

Effect of Valsartan on Combined Mortality and Morbidity End Point* in Overall

Population

Months

3 6 9 12 15 18 21 24 270

65

70

75

80

85

90

95

100

Probability of Event-Free

Survival

0

*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators.

Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

30

Valsartan

Placebo

P = 0.00913.2% risk reduction

CHARM-Overall CV death and non-CV death

0 1 2 3 years

5

10

15

20

25

30%

0

CV death

Non-CV death

Placebo

Candesartanup to 32mg

Placebo

Candesartan

HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006

p=0.45

3.5Number at risk

Candesartan 3803 3563 3271 2215 761

Placebo 3796 3464 3170 2157 743

Primary Endpoint: All-Cause MortalitySecondary Endpoints: CV Death, MI, or HFOther Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg bid

(n = 4885)

Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible(either clinical/radiologic signs of HF or LV systolic dysfunction)

Major Exclusion Criteria:— BP 100 mm Hg— Serum creatinine 2.5 mg/dL— Prior intolerance of an ARB or ACEI— Nonconsent

double-blind active-controlled

median duration: 24.7 monthsevent-driven

Noninferiority

Val Superior to Cap Cap Superior to Val

Noninferiority not Demonstrated

Cardiovascular Mortality and Morbidity:Valsartan vs. Captopril

0.8 1 1.2

Hazard Ratio(97.5% CI)

1.13

P Value(noninferiority)

noninferiority margin

CV Death(1657 events)

0.001

CV Death or HF(2661 events)

0.0001

CV Death or MI(2234 events)

0.00001

CV Death, MI, or HF(3096 events)

0.000001

VALUE: DesignElective titration to target BP (<140/90 mmHg)

Month 0.5 0 1 2 3 4 6 * 72

A 10 mg +HCTZ 25 mg

A 5 mg

A 10 mg +HCTZ 12.5 mg

A 10 mg

V 80 mg

V 160 mg

V 160 mg +HCTZ 12.5 mg

V 160 mg +HCTZ 25 mg

Amlodipine-based regimen

V 160 mg +HCTZ 25 mg + "Free" add-on

A 10 mg +HCTZ 25 mg + "Free" add-on

Valsartan-based regimen

ScreeningRandomisation End of treatment adjustment period

Rolloverfromprevious therapy(92%)

*Patient visits every 6 months for months 6–72.

Julius S et al. Lancet. June 2004;363:2022–31.

VALUE: Systolic Blood Pressure in Study


Valsartan (N= 7649)

Amlodipine (N = 7596)

135

140

145

150

155

mm

Hg

Months (or final visit)

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

01.02.03.04.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66

Months (or final visit)

5.0Difference in SBP Between Valsartan and Amlodipine

–1.0

VALUE: Outcome and SBP Differences at Specific Time Periods: Primary Endpoint

Time Interval(months)

Overall study

36–4824–3612–246–12

0–3

48−end

Favours amlodipine

1.0 2.00.5

PRIMARY ENDPOINT Odds Ratios and 95% CIs

SBPmmHg

1.41.61.82.0

3.8

1.7

2.2

3–6 2.3

Favours valsartan

4.0


For dose-responsive efficacy and excellent blood-pressure control1

1. Pool et al. Clin Ther 1998;20:1106-1114

Net

mea

n c

han

ge

in S

SB

P (

mm

Hg

)

Net

mea

n c

han

ge

in S

DB

P (

mm

Hg

)

0

-1

-2

-4

-3

-5

-6

-7

40 80 160 320

-3.9

-6.4

-5.1

-2.6-2.6

0

-1

-2

-4

-3

-5

-6

-7

40 80 160 320

-6.8

-9.0-8.6

-5.3

-8

-9

DIASTOLIC SYSTOLIC

Valsartan®Dose (mg) q.d.

Co-Diovan offers the additional efficacy you need for some patients1

1. Benz J R et al. J Hum Hypertens. 1998;12:861-866

2

2. Bremner PA et al. Circulation. 1998;98:2037-2042

-11.8

-8.8-8.6

0

-4.0

-8.0

-12.0

-16.0

-20.0

Diastolic DiastolicSystolic Systolic

-16.5

DIOVANValsartan

80 mg (n=99)

Co-DiovanValsartan/HCTZ

80 mg/12.5 mg (n=96)

mm

Hg

HIGH vs LOW Dose◙ ACEIs :

► NETWORK: No difference between 5, 10

and 20 mg Enalapril

► ATLAS: High dose Lisinopril:

signif. ↓ mortality + hospit. for CHF

◙ ARBs : Highest tolerated dose in Val-HeFT

and CHARM trials. Low dose in ELITE II

→ HEAAL trial: 50 mg vs 150 mg Losartan

ATLASMajor outcome findings

Primary endpoint 8% in all-cause mortality (non-significant trend: p=0.128)

Secondary endpoints 12% in combined all-cause mortality and all-cause hospitalisation

(p=0.002) 10% in cardiovascular mortality (non-significant trend: p=0.073) 8% in combined all-cause mortality and cardiovascular hospitalisation

(p=0.036) 9% in combined cardiovascular mortality and hospitalisation (p=0.027) 8% in fatal and non-fatal MI and hospitalisation for unstable angina

(p=0.374)

Post-hoc analysis 15% in combined all-cause mortality and hospitalisation for heart failure

(p<0.001)

‘High dose’ lisinopril versus ‘low dose’ lisinopril resulted in risk reductions of:

ATLAS compared with SOLVD

Treatments Reduction in risk Reduction in risk compared of death of death or

hospitalisation for HF

High dose vs.placebo (SOLVD) 16% 26%

Low dose vs. placebo(not studied) not known not known

High dose vs. low dose (ATLAS) 8% 15%

Use of low dose ACEi provides only about half of the benefit that can be achieved with high dose.

How to get it ?

• Achieve BP goals– difficult but feasible– multiple drugs needed

• Select appropriate agents and dosages– evidences on CV prevention with RAAS inhibitors are

overwhelming– only up-titration to high dosages seems to be effective


ADA Treatment Recommendations for Diabetic Patients with Hypertension

• Recommended target blood pressure

– Systolic <130 mm Hg

– Diastolic <80 mm Hg

• Drug therapy mandatory above 140 mm Hg systolic and 90 mm Hg diastolic

• Recommended first-line agents for patients with microalbuminuria or clinical albuminuria

– ARBs and ACE-IsARBs and ACE-Is

American Diabetes Association. Diabetes Care. 2002;25(Suppl 1):S71-S73.

Meta-analysis of Patients With Renal Dysfunction and Type 2 Diabetes (RENAAL, IDNT, IRMA 2 trials)

05

1015202530

Deaths % CV events %

ARBs (n = 1719)

Placebo (n = 1532)

Rouleau JL et al. Can J Cardiol. 2002

P = 0.22P = 0.22 P = 0.034P = 0.034

3535

4545

4040

3030

2525

2020

1515

1010

55

00

Subjects (%)

Subjects (%)

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

150 mg(n = 195)150 mg

(n = 195)300 mg

(n = 194)300 mg

(n = 194)

IrbesartanIrbesartan

24%24%

34%34%

21%21%

IRMA 2Normalization of urinary albumin excretion rate

Parving H-H et al. N Engl J Med 2001;345:870–8.Parving H-H et al. N Engl J Med 2001;345:870–8.

p = 0.006

HOPE and PEACE: new onset diabetes

0

2

4

6

8

10

12

HOPE PEACE

ACE-i Placebo

3.6%5.4%

9.8%

11.5%

HR 0.66 95% CI 0.51-0.85p <0.001

HR 0.83 95% CI 0.72-0.96p =0.014

100.5 (19.5)*103.1 (27.7)104.4 (28.5)4 Years

Diabetes incidence (follow-up fasting glucose 126 mg/dL)

Among baseline non-diabetics with baseline <126 mg/dL

Total

4 Years

Baseline

4 Years

Baseline

8.1%*9.8%*11.6%

93.3 (11.8)93.0 (11.4)93.1 (11.7)

121.5 (51.3)*123.7 (52.0)126.3 (55.6)

122.9 (56.1)123.1 (57.0)123.5 (58.3)

LisinoprilAmlodipineChlorthalidone

ALLHATBiochemical Results–

Fasting Glucose (mg/dL)

*P < 0.05 compared to chlorthalidone.

CHARM-Overall: New diagnosis of diabetes mellitus

years0

2

4

6

8

Proportion of patients (%)

p=0.020

HR 0.78 (0.64-0.96) p=0.020

0 1.0 2.0 3.0 3.5

Placebo

Candesartan

12

10 202 (7.4%)

163 (6.0%)

Candesartan 2715 2565 2395 1662

Placebo 2721 2501 2304 1622

LIFE: new onset diabetes

0

5

10

15

20

LIFE

Losartan Atenolol

13.0%

17.4%

HR 0.75 95% CI 0.63-0.88p =0.001

VALUE: Incidence of New-onset DiabetesN

ew-O

nset

Dia

bete

s (%

of

pati

ents

in

tre

atm

ent

grou

p)


0

2

4

6

8

10

12

14

Valsartan-based Regimen(n = 5254)

Amlodipine-based Regimen(n = 5168)

13.1%

16.4%

23% Risk Reduction With Valsartan

16

18

P < 0.0001

NAVIGATORNateglinide and Valsartan in Impaired Glucose

Tolerance Outcomes Research

• Multinational trial in 9524 IGT patients randomized to either placebo or:– Nateglinide 60 mg tid ac– Valsartan 160 mg/d– Combination of nateglinide (60 mg tid ac) and valsartan (160

mg/d)

• Study duration of 5-6 years• Represents the largest diabetes prevention study

to date and the only one powered to assess CVD

NAVIGATOR: Primary Objectives

• Evaluate the effect of nateglinide, valsartan or the combination on progression to diabetes in patients with IGT

• Evaluate the effect of nateglinide, valsartan or the combination on the composite CV end point (CV mortality, non-fatal MI, stroke, unstable angina, revascularization)

Utility of Antihypertensives by Co-morbidity

nephroprotectionnephroprotection+ ACE-I, ARB+ ACE-I, ARB+ loop diuretics+ loop diuretics

Renal insufficiencyRenal insufficiency

resistance to urinary flowresistance to urinary flow+ + 11-blocker-blockerBenign prostatic hyperplasiaBenign prostatic hyperplasia

nephroprotectivenephroprotectivemetabolically neutral, metabolically neutral, prognosis prognosis

ACE-I, ARBACE-I, ARBcardioselective beta-blocker cardioselective beta-blocker thiazide diureticsthiazide diuretics

Metabolic syndrome, diabetes Metabolic syndrome, diabetes mellitusmellitus

prognosisprognosisACE-I, ARBACE-I, ARBbeta-blockerbeta-blocker

Post myocardial infarctionPost myocardial infarction

antianginal, antianginal, prognosisprognosisbeta-blockerbeta-blockerACE-IACE-I

Coronary artery diseaseCoronary artery disease

re- and afterload re- and afterload prognosisprognosis preload preload reduction in mortality post-MIreduction in mortality post-MI

ACE-I, ARBACE-I, ARBdiuretics diuretics beta-blockersbeta-blockers

Heart failure Heart failure

ReasoningReasoningDrug ClassesDrug ClassesCo-MorbidityCo-Morbidity

Braun J, Dorman A. eds. Clinical Guide to Internal Medicine. 8th ed. München: Urban & Fischer; 2001. Braunwald E, Zipes DP, Libby P. eds. Heart Disease. 6th ed. WB Saunders; 2001:972.The HOPE Study Investigators. N Engl J Med. 2000;342:145-153. American Diabetes Association. Diabetes Care. 2002;25(Suppl 1):S71-S73. WHO

Guidelines subcommittee. J Hypertens. 1999;17:151-183. JNC VI. Arch Intern Med. 1997;152:2413-2446.

“The objective of antihypertensive therapy should be to not only lower the blood pressure but to prevent the lethal and disabling cardiovascular sequelae.”

Kannel WB. Eur Heart J. 1992;13(suppl G):34–42.

How to get it ?• Achieve BP goals

– difficult but feasible– multiple drugs needed

• Select appropriate agents and dosages– evidences on CV prevention with RAAS inhibitors are overwhelming– only up-titration to high dosages seems to be effective

• Take into account comorbidities– RAAS inhibitors seem to prevent diabetes and related CV complications

• ARB (specifically Valsartan) is the most studied class of drugs along the CV continuum

PEACE trial: Other Outcomes

0.0480.77 (0.60-1.00)3.22.5CHF hospitalization

0.130.89 (0.76-1.04)8.17.2Death (any cause)

0.0140.83 (0.72-0.96)11.59.8New diabetes

1.7

2.8

Trandolapril n=4158

%

2.2

3.7

Placebo n=4132

%

0.0180.75 (0.59-0.95)CHF hospitalization or CHF death

0.090.76 (0.56-1.04)Stroke

P-value

Hazard Ratio (95% CI)

Outcome

NEJM 2004;351:2058-68

VALUE: Primary Composite Cardiac Endpoint

14

12

10

8

6

4

2

0

Time (months)

0 6 12 18 24 30 36 42 48 54 60 66

Pro

port

ion

of P

atie

nts

W

ith

Fir

st E

ven

t (%

)Valsartan-based regimen

Amlodipine-based regimen

HR = 1.03; 95% CI = 0.94–1.14; P = 0.49


Number at risk

Valsartan

Amlodipine 7596

7649

7469

7459

7424

7407

7267

7250

7117

7085

6772

6732

6955

6906

6576

6536

5959

5911

3725

3765

1474

1474

6391

6349

High-risk hypertensive patientsHigh-risk hypertensive patients SBP >140 mm Hg DBP >90 mm Hg

OR Took medication for hypertension and

at least 1 additional CAD risk factor Age >55 years

RandomizationRandomization

Eligible for lipid-lowering Not eligible for lipid-lowering

Randomize

Pravastatin Usual care

Follow for occurrence of CAD until death or end of study (mean 4.9 years)• Primary end point – Fatal coronary heart disease and nonfatal MI• Secondary end points – All-cause mortality, stroke, and major cardiovascular disease events (CHF, coronary revascularization, angina, and peripheral vascular disease)

ALLHAT: Study Design

Davis BR et al. Am J Hypertens. 1996;9:342-360.

Chlorthalidone 12.5-25 mg/dChlorthalidone 12.5-25 mg/d

Amlodipine 2.5-10 mg/dAmlodipine 2.5-10 mg/d

Lisinopril 10-40 mg/dLisinopril 10-40 mg/d

Doxazosin 2-8 mg/dDoxazosin 2-8 mg/d(N(N = 42,418)= 42,418)

Add-on medicationsStep 2Step 2: reserpine, clonidine, atenololStep 3Step 3: hydralazine

PLASMA RENIN LEVELS AFTER 2 AND 4 WEEKS OF TREATMENT WITH

DIFFERENT AT-1R BLOCKERS

0

35

70

105

140

2 Weeks 4 Weeks

Placebo Telmisartan 40 mg Losartan 50 mg Valsartan 80 mg

pg/ml

* * ***

**

* p < 0,05 ** p < 0,01 vs placeboFogari et al. Current Ther Res 2002; 63 : 1-14

0

2

4

6

8

10

12

control candesartan

10.310.3％％

7.47.4％％

（％)

--2828 ％％

SCOPE STUDYNON-FATAL STROKE

IN ELDERLY PATIENTS

Lithell et al. J Hypertens 2003; 21: 875-836

( n = 4964 )

EFFECT OF VALSARTAN ON INSULIN SENSITIVITY AND PLASMA LEPTIN IN

HYPERTENSISIVE OBESE PATIENTSSBP

100

120

140

160

Valsartan Felodipine

HOMA-R

2

3

4

5

6

7

8


PLASMA LEPTIN

20

30

40


Placebo Treatment

DBP

70

90

110


ng/ml

* *

****

****

( n = 80 )

mmHg mmHg

* p < 0,05 ** p < 0,01 Fogari et al. Hyperten Res 2004 in press

CHARM Val-HeFTAll Added Alternative All With

ACEI

(93%)

Non-ACEI

(7%)

N= 7601 2548 2028 5010 4644 366

Dose 32mg 320mg

All cause mortality RR

NS NS 33% p=0.017

-Combined all cause M&M

-CV death and/or hospitalization RR

16% p<0.0001

15%p<0.011

23%P=0.0004

13.2%p=0.009

13.2%p=0.009

44.0%P<0.001

Hospitalization for CHF

21%p<0.0001

17%p<0.014

23%p<0.0001

27.5%p<0.001

27.5%p<0.001

53%p<0.001

CV death 12%p=0.012

16%p=0.029

15%p=0.072

NDA NDA 24%p<0.074

use of the optimal dose of arbs in hypertension and cv diseases ass. prof. roland kassab head of...

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end of study