Management of The Patients with Hypertension and High ... 16/songsuk...Management of The Patients with Hypertension and High Risk Cardiovascular Disease Songsak Kiatchoosakun, MD.

Management of The Patients with Hypertension and High Risk

Cardiovascular Disease

Songsak Kiatchoosakun, MD.Cardiology, MedicineKhon Kaen University

CVD and Hypertension: Worldwide Morbidity and MortalityCardiovascular disease accounted for 16.6 million deaths in 2000

7.3 million ischemic heart disease deaths

5.4 million stroke deaths

High blood pressure is associated with an estimated 7.1 million deaths

Estimated 690 million persons have hypertension; most remain untreated or uncontrolled

Hypertension

*Men aged 35-57 years followed for a mean of 12 years.Neaton et al. Arch Intern Med. 1992;152:56-64.

CHD Death Rate per 10,000 Person-Years

100+100+

8080--8989

7070--7474<70<70

7575--7979

9090--9999

Effect of Systolic BP and Diastolic BP on CHD Mortality

48.3

37.434.7 43.8

38.1

80.631.031.0

25.525.524.624.6

25.325.325.225.2

24.924.9

23.8

16.913.9

12.812.6

11.8

20.6

10.311.8

8.88.5

9.2

<120120-139

140-159160+

Systolic BP(mm Hg)

Diastolic BP(mm Hg)

: MRFIT Study (N=316,099)*

Classification of HypertensionDefinitions and Classification of Blood Pressure (BP) Levels (mmHg)

( European Society of Cardiology 2007)

Category Systolic DiastolicOptimal <120 and <80

Normal 120-129 and/or 80-84

High normal 130-139 and/or 85-89

Grade1 hypertension 140-159 and/or 90-99

Grade2 hypertension 160-179 and/or 100-109

Grade3 hypertension ≥ 180 and/or ≥ 110

Isolated systolic hypertension ≥ 140 and <90

Establishing blood pressure levelsIdentifying secondary causes of hypertensionEvaluating the overall cardiovascular risk

Other risk factorsTarget organ damageConcomitant diseases

Assessment of Patient with HT

Blood Pressure Measurement

Sir, your blood pressure is OK.

Secondary Cause of Hypertension

Sings suggesting secondary hypertensionFeatures of Cushing syndromeSkin stigmata of neurofibromatosis (pheochromocytoma)Palpation of enlarged kidneys (polycystic kidney)Auscultation of abdominal murmurs (renovascular hypertension)Diminished and delayed femoral pulses and reduced femoral BP (aortic coarctation, aortic disease)

Total Cardiovascular Risk

ConceptsSmall number of patients have hypertension aloneBlood pressure and metabolic risk factors potential each other and leading to greater cardiovascular riskGoals for treatment and treatment strategies are different between high risk and low risk patients

Patients With Hypertension Are Likely To Have Additional CV Risk Factors

Kannel WB. Am J Hypertens. 2000;13:3S-10S.

None19%

1 RF26%2 RFs

25%

3 RFs22%

4+ RFs8% None

17%

1 RF27%

2 RFs24%

3 RFs20%

4+ RFs12%

WomenMen

The Threat of Global CV Risk

Risk shown above is compared with risk for a 40-year-old male nonsmoker with TC 4.7 mmol/L (185 mg/dL), SBP 120 mm Hg, and no glucose intolerance, who is ECG-LVH negative and whose probability of developing CVD is 15/1000 (1.5%) in 8 years

Kannel W. In: Hypertension: Pathophysiology and Treatment. New York: McGraw-Hill, Inc.; 1977:888-909.

DyslipidemiaTC 5.4 mmol/L

(210 mg/dL)X1.3

HypertensionSBP 165 mm HgX1.9

Glucose intoleranceX1.8

X2.6

X4.5X3.5 X2.3

DyslipidemiaTC 6.1 mmol/L

(235 mg/dL)X1.7

HypertensionSBP 195 mm HgX3.0

SmokingX1.7

X5.3

X8.7X5.2 X2.9

Factors Influencing Prognosis (1)Risk factors

Systolic and diastolic BP levels and pulse pressure (in elderly)Age (M > 55 years; W > 65 years)SmokingDyslipidemia- TC > 5.0 mmol/l (190 mg/dl) or:- LDL – C >3.0 mmol/l (115 mg/dl) or:- HDL – C: M < 1.0 mmol/l (40 mg/dl), W <1.2 mmol/l (46 mg/dl) or:- TG > 1.7 mmol/l (150 mg /dl)Fasting plasma glucose 5.6 – 6.9 mmol/l (102 -125 mg /dl)Abdominal obesity (waist circumference > 102 cm (M), >88 cm (W)Family history of premature CV disease (M at age <55 years; W atage <65 years)

Factors Influencing Prognosis (2)Sub-clinical organ damage

LVH by ECG or Echocardiography (LVMI M > 125 g/m2, w > 110 g/m2)Carotid wall thickening (IMT > 0.9 mm) or plaqueAnkle/brachial BP index <0.9Slight increase in plasma creatinine:M: 115 – 113 umol/l (1.3 – 1.5 mg/dl)W:107 – 124 umol/l (1.2 – 1.4 mg/dl)Low estimated glomerular filtration rate+ (60 ml/min/1.73 m2) or creatinine clearance (< 60 ml/min)Microalbuminuria 30 – 300 mg/ 24 h or albumin –creatinine ratio: > 22 (M); or > 31 (W) mg/g creatinine

Rike maximal for concentric LVH (left ventricular hypertrophy): increased LVMI(left ventricular mass index) with a wall thick ness/ radius ratio > 0.42.

Factors Influencing Prognosis (3)Established CV or Renal Disease

Cerebrovascular diseaseHeart disease: CAD, CHFRenal disease: diabetic nephropathy; renal impairmant (creatinine;M > 133, W > 1 24 mmol/l); proteinuria (> 300 mg/24 h)Peripheral artery disease Advanced retinnopathy: haemorrhages or exudates, papilledema

Diagnostic Evaluation

Blood Test

• FBS• Lipid panel• Renal function• Electrolyte

Waist Circumference

Electrocardiography

Proteinuria

Echocardiography: LV Hypertrophy

Carotid Plaque

Total Cardiovascular Risk

High/Very High Risk SubjectsBP > 180 mmHg systolic and/or > 110 mmHg diastolicSystolic BP > 160 mmHg with low diastolic BP ( < 70 mmHg)Diabetes mellitusMetabolic syndrome> 3 cardiovascular risk factorsOne or more of the following sub-clinical organ damages:- LV hypertrophy

- Carotid plaque detected by ultrasound- Renal impairment/micro-albuminuria or proteinuria

Established cardiovascular or renal disease

Goals of TreatmentPrimary goal is to achieve maximum reduction in the long term total risk of cardiovascular diseaseBP should be reduce to at least below 140/90 mmHgTarget BP should be at least <130/80 mmHg in diabetics and in high or very high risk patients such as stroke, myocardial infarction, renal dysfunction, proteinuriaIn order to more easily achieve goal BP, antihypertensive treatment should be initiated before significant cardiovascular damage develops

Treatment Strategies

Lifestyle changes

Smoking cessation

Moderation of alcohol consumption

Sodium restriction

Other dietary changes

Weight reduction

Physical exercise

Antihypertensive Therapy

Five major classesDiureticsBeta-blockerACE inhibitionAngiotensin receptor antagonistCalcium antagonist

Effect of Antihypertensive Therapy%

Red

uctio

n

MacMahon SW et al. Prog Cardiovasc Dis. 1986;29(suppl 1):99–118.

60

50

40

30

20

10

0

48%

16%

CerebrovascularDisease

Coronary HeartDisease

Systematic overviews showed that reductions inblood pressure of about 10-12 mm Hg systolicand 5-6 mm Hg diastolic conferred relativereductions in stroke risk of 38% and in risk ofcoronary heart disease of 16% within justa few years of beginning treatment.

Clinical Research Questions in Hypertension

Is blood pressure lowering beneficial ?

Does it matter how elevated bloodpressure is lowered ?

Hypertension Treatment Significantly Reduced Mortality and Morbidity

VA Cooperative Study Group – Estimated Cumulative Incidence of All Morbid Events Over 5 Years

Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.

0

10

20

30

40

50

60

0 1 2 3 4 5Years

Estim

ated

Cum

ulat

ive

Inci

denc

e of

All

Mor

bid

Even

ts (%

)

Control - Placebo

Active Treatment Groups -Diuretic-based regimen and hydralazine

37% risk reduction

•380 male patients •diastolic blood pressure (BP) averaging 90 -114 mmHg

SHEP Trial: Endpoints

SHEP Cooperative Research Group. JAMA. 1991;265:3255; Kostis et al. JAMA. 1997;278:212-216.

Active Therapy (diuretic, beta-blocker vs Placebo)

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

Stroke CHD CHF CVD Death

-37%-25%

-54%

-32%

-13%

Rel

ativ

e R

isk

(95%

CI)

P=NS

In hypertension, beta blockers and diuretics have proven risk reduction in cardiovascular morbidity and mortality vs. placebo (STOP, HEP, MRC)Hypertension guidelines recommend beta blockers or diuretics as one of the initial treatments for hypertension

JNC-VII Guideline

Beta-blockers and Diuretic Lower Risk of Cardiovascular Mortality

Diuretic / Beta-blocker

The benefits of diuretic therapy on coronary artery disease were less than than expectedMetabolic side effects of diuretic/beta-blocker mitigated the beneficial effect of blood pressure reduction The beneficial effect of new treatment may beyond the blood pressure lowering effect

VasoconstrictionVasoconstriction Sodium RetentionSodium Retention

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Angiotensin IIAngiotensin II

AT I receptorAT I receptor

ReninRenin

AngiotensinAngiotensinConvertingConverting

EnzymeEnzyme

Renin-Angiotensin-Aldosterone (RAAS)and Hypertension

Increase blood pressure

Angiotensin I

Angiotensinogen(Liver)

AT1 AT2

Angiotensin II

ACE-inhibitor

Bradykinin

Peptides

Manipulation of Ang II generation

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

ACE InhibitionBlood pressure loweringBeyond blood pressure

Anti-atherosclerotic effectsImprovement in vascular endothelial function LV hypertrophy reduction

Reduce new onset of diabetes

Reduce cardiovascular complications of hypertension

The Heart Outcomes Prevention Evaluation Study: HOPE Study

Aim: Effect of Ramipril (up to 10mg/d) vsplacebo on CV death, MI or stroke (primary)

Design:Randomized double blind, Wide entry criteria, large, simple trial

Size: 9541 patients followed for 4 to 6 yearsHeart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

HOPE Study Population: “Typical” Office Practice Patients

Patients did not have clinical of heart failure

47% of had high blood pressure

Patients were 55 years or older

CV events11% had previous stroke52% had previous MI

Vascular disease80% had history of CAD42% had history of PVD

Diabetes39% had diabetes + 1 or more CVD risk factors

The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

HOPE: Primary Outcome Reductions in MI, Stroke, or Cardiovascular Death

Note: Trial halted early due to the highly significant risk reductions seen with Ramipril

0.200.20

0.150.15

0.100.10

0.050.05

00

00 500500 10001000 15001500

22%22%ReductionReductionin Eventsin EventsP=.0001*P=.0001*

PlaceboPlacebo

RamiprilRamipril

Days of FollowDays of Follow--upup

% o

f P

atie

nts

Rea

chin

g E

nd

poi

nts

15%15%Reduction Reduction in Events at in Events at 1 year1 year

HOPE Study: Results (contd.)

-26%

-20%

-32%

-15%

-37%

-23%

-16%

-34%-40-35-30-25-20-15-10-50

CV death

MI Stroke

Revasc

Cardiac a

rrest

Heart fa

ilure

Total m

ortality

Type 2

diabete

s

% r

isk

redu

ctio

n

N Engl J Med 2000; 342: 145-153

HOPE: Dose-dependent Effects of Ramiprilon LV Mass and Function

8.21 7.86

–3.53–6–4–2

02468

10 5.31

2.9

–1.9–3–2–1

0123456

∆ LV end

systolic volume(mL)

Placebo (n = 151) Ramipril 2.5 mg (n = 149) Ramipril 10 mg (n = 146)

∆ LV mass

(g)

Mean baseline LVEF 58% in all groups

Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.

P Trend = 0.03 P Trend = 0.001

HOPE:ConclusionsIn people with high risk for CVD, addition of ramipril to other effective therapies prevents:

CV death, strokes and MITotal mortalityRevascularization

The benefit is beyond the effect on BP (3/2 mmHg)

HOPE-TOO: Primary Outcome (CV death, MI, Stroke)

30

RRR = 17%P = 0.0002

0 1 2 3 4 5 6 70

RRR = relative risk reduction HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Placebo

Ramipril

Years

Primary outcome

(% HOPE-TOO patients)

25

20

15

10

5

46524645

44324456

42044256

39814079

36473789

27192819

19232075

15501731

PlaceboRamipril

n

HOPE-TOO begins

Main HOPE study ends

HOPE-TOO: Additional Reduction in New-onset Diabetes

HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

12

4

6

2

0

1 2 3 4

8

10

5 6 7

Placebo

Ramipril

Years

RRR 31% P = 0.0006

HOPE-TOO begins


28832837

28032763

27042672

26002587

23922431

18131853

12691324

10211092

New-onsetdiabetes

(% HOPE-TOO patients)

PlaceboRamipril

n

SECURE: Dose-dependent Effect of Ramipril on Carotid Atherosclerosis

Lonn E et al. Circulation. 2001;103:919-925.

0

0.005

0.010

0.015

0.020

0.025

0.022

0.018

0.014

NS

37% Reduction

P = 0.028

Ramipril10 mg

Ramipril2.5 mg

Placebo

Slope of the mean

maximum carotid-intima

thickness (mm/y)

Years

Prob

abili

ty o

f Eve

nt

00.05

0.150.2

0.250.3

0 1 2 3

0.350.4

4

ACE-IPlacebo

OR: 0.74 (0.66–0.83)26 % reduction

0.1

Flather MD, et al. Lancet. 2000;355:1575–1581

SAVERadionuclideEF < 40%

AIREClinical and/or radiographic signs of HF

TRACEEchocardiogramEF < 35%

ACE Inhibitor Evidence: Post MI with HF

ACE-I=Angiotensin converting enzyme inhibitors, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio

Comparison of ACE Inhibitors and Calcium Antagonist

Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000;356:1955

ACE inhibitors based therapy mayreduce risk of CAD and heart failure

0.5 1.0 2.0

Stroke

Coronary heart disease

Heart failure

Total mortality

Favor ACEI Favor calcium antagonistRelative risk

Angiotensin I

Angiotensinogen(Liver)

AT1 AT2

Angiotensin IIARB

AT1 receptor blocker

Manipulation of Ang II generation

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

The Losartan Intervention For Endpoint Reduction in Hypertension

Study (LIFE Study)9,193 hypertensive patients with LVH, aged 55-80 yearsMean 4.8-year follow-up44,119 patient-years of follow-up945 study sites in 7 countries

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

0

2

4

6

8

10

12

14

16

Prop

ortio

n of

pat

ient

s with

firs

t eve

nt (%

)Composite of CV death, stroke and MI

Losartan

Atenolol

Study Month 0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13.0%, p=0.021Unadjusted Risk Reduction 14.6%, p=0.009

LIFE: Primary Composite Endpoint


Number at risk

Stroke

Losartan

Atenolol

Adjusted Risk Reduction 24.9%, p=0.001Unadjusted Risk Reduction 25.8%, p=0.0006

Study Month0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8


Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897

Fatal and non-fatal stroke

Prop

ortio

n of

pat

ient

s with

firs

t eve

nt (%

)

Number at risk

24.9 %

LIFE:Myocardial Infarction and CV Mortality

Cardiovascular mortality


AtenololLosartan

Prop

ortio

n of

pat

ient

s (%

)

Adjusted RR 11.4%, p=0.206Unadjusted RR 13.3%, p=0.136

Fatal and non-fatal MI

0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8

Prop

ortio

n of

pat

ient

s w

ith fi

rst e

vent

(%)

Adjusted RR -7.3%, p=0.491Unadjusted RR -5.0%, p=0.628

AtenololLosartan


0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8


Study Month

Study Month

Results from ASCOTResults from ASCOT--BPLA:BPLA:AAnglonglo--SScandinavian candinavian CCardiac ardiac

OOutcomes utcomes TTrialrial––BBlood lood PPressure ressure LLowering owering AArmrm

VBWG

ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial

Sever PS et al. Lancet. 2003;361:1149-58.Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

Study 1: ASCOT-LLADouble-blind, randomized, placebo-controlled trial of a lipid-lowering agent in a sample of the total ASCOT patient population

Study 2: ASCOT-BPLAProspective, randomized, open, blinded endpoint (PROBE) design comparing two antihypertensive regimens in the total ASCOT patient population

VBWG

ASCOT-BPLA: Study design

Design: Double-blind, placebo controlled, randomized

Population: N = 19,257 with hypertension and ≥3 other CV risk factors

Treatment: Amlodipine 5–10 mg ± perindopril 4–8 mg prn(n = 9639)

Atenolol 50–100 mg ± bendroflumethiazide1.25–2.5 mg/potassium prn (n = 9618)

Primary outcome: Nonfatal MI (including silent MI) and fatal CHD

Secondary outcome: All-cause mortality, stroke, nonfatal MI (excluding silent MI), all coronary events, CV events/procedures, CV mortality, fatal/nonfatal HF

VBWG

ASCOT-BPLA: Reduction in Primary Outcome (nonfatal MI and fatal CHD)

Number at riskAmlodipine-based regimen 9639 9475 9337 9168 8966 7863(429 events)Atenolol-based regimen 9618 9470 9290 9083 8858 7743(474 events)

Proportionof events

(%)

6

2

4

0

8

1 2 3 4

10

5 60Time since randomization (years)

HR = 0.90 (95% CI, 0.79–1.02) RRR = 10%P = 0.1052

Atenolol-based regimen*Amlodipine-based regimen†

Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

VBWG

*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn

ASCOT-BPLA: Reduction in Fatal and Nonfatal stroke

Number at riskAmlodipine-based regimen 9639 9483 9331 9156 8972 7863(327 events)Atenolol-based regimen 9618 9461 9274 9059 8843 7720(422 events)

Proportionof events

(%)

6

2

4

03 4

8

1 2

10

50Time (years)

6

Atenolol-based regimen*Amlodipine-based regimen†

HR = 0.77 (95% CI, 0.66–0.89)RRR = 23%P = 0.0003

VBWG


*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn

ASCOT-BPLA: Overall Results

Study stopped prematurely after 5.5-year median follow-up because of higher death rate in assigned atenolol-based-regimen group

Group receiving amlodipine-based regimen had nonsignificant 10% reduction in primary outcome (nonfatal MI plus fatal CHD) and significant reductions in nearly all secondary CV endpoints and new-onset diabetes


VBWG

ASCOT-BPLA: SummaryVBWG

Dahlöf B et al. Lancet. 2005;366:895-906.Poulter NR et al. Lancet. 2005;366:907-13.

Newer antihypertensive drug regimens should be considered in preference to older beta-blocker ± diuretic therapiesAmlodipine ± perindopril showed reductions in:

Major CV events 16%New-onset diabetes 30%Stroke 23%Mortality 11%

ASCOT results support the use of newer drugs, in multi-drug combinations, to modify risk factors and/or metabolic disturbances, especially in patients with complicated hypertension

New Onset Diabetes: Impact of Blood Pressure Lowering Drugs

Cardiovascular Events inTreated Hypertensive Subjects

0

1

2

3

4

5

6

A B C

A - without diabetes B - new onset diabetesC - previously known diabetes

Rat

e of

eve

nts

(per

100

pat

ient

yea

rs)

.97

3.90

4.70

Verdecchia, Hypertens 2004;43:963-968

Total number of CV events - 63

Risk of DM among 3804 Hypertensive Patientswith Various Antihypertensive Medications

Rx Hazard Ratio*

None 1.0ACEI 0.9B-Blocker 1.25**CCB 1.17Thiazides 0.95

* adjusted for age, race, BMI, CV risk factors, etc.** significant difference

Gress, et al. NEJM 2000;342:905-12

Pharmacological Therapy in Hypertension

Choice of antihypertensive drugsThe main benefits of antihypertensive therapy are due to lowering blood pressureBeta-blockers especially in combination with thiazide diuretic, should not be used in patients with metabolic syndrome or at high risk of diabetes

ESC guideline 2007

British Hypertension Society Guideline 2006

ACEI or ARB + CCB+ Diuretic

Add beta-blocker or alpha-blocker

Age < 55

ACEI or ARB

Add CCB

Age > 55 or black

CCB or Diuretic

Add ACEI or ARB

Conditions Favoring use of SomeAntihypertensive Drugs versus Others

Thiazide diuretics Beta-blockers- Isolated systolic HT - Angina pectoris- Heart failure - Post-myocardial infarction

- Heart failure- Tachyarrhymias

ACE inhibitors Angiotensin receptor antagonists- Heart failure - Heart failure- LV dysfunction - Post-myocardial infarction- Post-myocardial infarction - Diabetic nephropathy- Diabetic nephropathy - Proteinuria- Non-diabetic nephropathy - LV hypertrophy- LV hypertrophy - Atrial fibrillation- Carotid atherosclerosis - Metabolic syndrome- Proteinuria/Microalbuminuria - ACEI-induced cough- Metabolic syndrome

Conditions Favoring use of SomeAntihypertensive Drugs versus Others

Calcium antagonists Calcium antagonists(dihydropyridines) (verapamil/diltiazem)- Isolated systolic hypertension - Angina pectoris

(elderly) - Carotid atherosclerosis- Angina pectoris - Supraventricular tachycardia- LV hypertrophy- Carotid/Coronary

Atherosclerosis- Pregnancy- Hypertension in blacks

Diuretics (anti-aldosterone) Loop diuretics- Heart failure - End stage renal disease- Post-myocardial infarction - Heart failure

Thank You for Your Attention

VALUEValsartan

Antihypertensive Long-Term Use

Evaluation

VALUE: Patient Population

Treated or untreated hypertensive patientsentry criteria for untreated hypertension:160–210 mmHg systolic, 95–105 mmHg diastolic

Age ≥50 years, male or female

High-risk for cardiac eventsone or more defined risk factors or diseases

Mann J, Julius S. Blood Press. 1998;7:176–183.

VALUE: Primary Composite Cardiac Endpoint14

12

10

8

6

4

2

0

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

Prop

ortio

n of

Pat

ient

s W

ith F

irst

Eve

nt (%

)Valsartan-based regimenAmlodipine-based regimen

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

Julius S et al. Lancet. June 2004;363.

Number at riskValsartanAmlodipine 7596

7649

7469

7459

7424

7407

7267

7250

7117

7085

6772

6732

6955

6906

6576

6536

5959

5911

3725

3765

1474

1474

6391

6349

HOPE (Heart Outcomes Prevention Evaluation) Study

Patients > 55 years with a history of- CAD or stroke or peripheral artery disease- Diabetes plus at least one other CV risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking or microalbuminuria)Patients did not have heart failure or LV dysfunction9297 patients received ramipril or placeboTreatment duration: 4.5 years

Dyslipidemia Is More Common in Patients With Hypertension

*Hypertension defined as BP ≥ 150/ ≥ 95 mm HgMacMahon M, et al. Arteriosclerosis. 1985;5:391-396.

18 19

28

3735 36

0

5

10

15

20

25

30

35

40

Men Women

Normal BPHigh BPAntihypertensive Rx

Patie

nts

with

TC

≥6.

5 m

mol

/L(≥

250

mg/

dL) (

%)

Monotherapy versus Combination Therapy Strategies

Choose between

Mild BP elevation

Low/moderate CV risk

Conventional BP target

Marked BP elevation

High/very high CV risk

Lower BP target

Two-drug combination

at low dose

Previous agent Switch to different agent

at full dose at low dose

Previous combination Add a third drug

at full dose at low dose

Full dose

Mono-therapy

If goal BP not achieved

If goal BP not achieved

Single agent

at low dose

Two-to three-drug

Combination at full dose

Two-three drug combination

at full doseESC guideline 2007

Possible Combinations Between Some Classes of Antihypertensive Drugs

VALUE: Incidence of New-onset DiabetesN

ew-O

nset

Dia

bete

s (%

of p

atie

nts i

n tr

eatm

ent g

roup

)

Julius S et al. Lancet. June 2004;363.

0

2

4

6

8

10

12

14

Valsartan-based Regimen(n = 7649)

Amlodipine-based Regimen(n = 7596)

13.1%

16.4%

23% Risk Reduction With Valsartan

16

18

P < 0.0001

Rationale

Cardiovascular (CV) disease continues to be the chief cause of mortality and morbidity worldwide

Most of this is due to coronary heart disease (CHD)

Multiple risk factors have synergistic effects in the pathogenesis of CV disease

Combination treatment regimens using ≥2 agents are recommended to reach target BP goals

Limited outcome data have led to an investigation comparing standard vs newer antihypertensive treatment options

VBWG

0 0.5 1 1.5 2

Cardiovascular death (0.86; 0.72-1.03)

Non-fatal MI (0.78; 0.20-0.90)

Cardiac arrest (0.54; 0.20-1.47)

Combined endpoint (0.80; 0.71-0.91)

13,655 patients with CAD and presumed normal left ventricular function randomized to perindopril (8 mg) or placebo for 4.2 years

ACE Inhibitor Evidence: CAD

European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA)

Favors Perindopril Favors Placebo

EUROPA Investigators. Lancet 2003;362:782-788

ACE-I=Angiotensin converting enzyme inhibitors, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction

ACE Inhibitor Evidence: CADPrevention of Events with Angiotensin Converting Enzyme

Inhibition (PEACE) TrialP

rimar

y E

nd P

oint

(%)*

30

25

20

15

10

5

00 1 2 3 4 5 6

Years After Randomization

PlaceboTrandolapril

PEACE Trial Investigators. NEJM 2004;351:2058-2068

*Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization

8,290 patients with stable coronary artery disease and normal left ventricular function randomized to trandolapril (4 mg) or placebo for 4.8 years

HOPE-TOO: Rationale

• HOPE-TOO was an extension of the HOPE trial, which examined the effects of ACE inhibition in reducing major CV events in high-risk patients with vascular disease or diabetes

• HOPE-TOO was designed to assess whether the CV and metabolic benefits of ramipril were sustained over time and occurred in subgroups based on varying risk and concomitant treatment


HOPE-TOO: Study Design

4528 HOPE patients at 174 centers who agreed to further follow-up

Blinded treatment ended and patients were advised to use ACEI

2.6-year post-trial extension

ACEI use during extensionHOPE ramipril arm (n = 2317): 72% HOPE placebo arm (n = 2211): 68% >90% of all HOPE-TOO patients used ramipril

Heart Outcomes Prevention Evaluation–The Ongoing Outcomes


Major CV Events and New Diagnosis of Diabetes

No. of patients (%)

New diagnosis of diabetes

Revascularization

Stroke

CV death

MIMI, stroke, or CV death

Ramipril(n = 3393)

Placebo(n = 3393)

699 (20.6)485 (14.3)

174 (5.1)

327 (9.6)

767 (22.6)

152 (7.3)

820 (24.2)

581 (17.1)

215 (6.3)

374 (11.0)

880 (25.9)

216 (10.3)

RR (95% CI) P*

0.83 (0.75–0.91)

0.81 (0.72–0.92)

0.79 (0.65–0.97)

0.86 (0.74–1.00)

0.84 (0.76–0.92)

0.69 (0.56–0.85)

0.0002

0.0007

0.023

0.045

0.0003

0.0006

*Calculated by log-rank test and data on all participants in the study extension, censored for period of observation


HOPE-TOO: Effect of ACEI on Major CV Events and New-onset Diabetes

No. of HOPE patients (%)

New diagnosis of diabetes

Revascularization

Stroke

CV death

MI

MI, stroke,or CV death

1.31.21.11.00.90.80.70.60.50.40.3 1.4 1.5

Ramipril(n = 2317)

Placebo(n = 2211)

RR (95% CI)

220 (7.9)

146 (5.1)

59 (2.0)

133 (4.4)

235 (9.1)

48 (2.7)

225 (8.4)

169 (6.1)

56 (1.9)

126 (4.2)

259 (10.5)

70 (4.0)

*Event rates were calculated as proportions of events in those study participants who were event-free at the end of the in-trial period.

Event*


HOPE-TOO: Additional Reduction in MI


25

RRR = 19%P = 0.0007

00 1 2 3 4 5 6 7

Placebo

Ramipril

MI(% HOPE-TOO

patients)

20

15

10

5

Years46524645

44744484

42824309

40884159

37703875

28142900

19992137

16121791

PlaceboRamipril

n

HOPE-TOO begins


HOPE-TOO: Sustained Reduction in Stroke


10

RRR = 21%P = 0.023

0

Placebo

Ramipril

8

6

4

2

Years46524645

45234539

43674391

41884263

38874000

29533011

21152225

17341876

0 1 2 3 4 5 6 7Placebo

Ramipril

n

Stroke(% HOPE-TOO

patients)

HOPE-TOO begins


HOPE-TOO: Sustained Reduction in CV Death


15

RRR = 14%P = 0.045

0

Placebo

Ramipril

10

5

Years46524645

45694567

44534448

43094346

40274097

30613100

22032295

18081946

0 1 2 3 4 5 6 7PlaceboRamipril

n

CV death(% HOPE-TOO

patients)

HOPE-TOO begins


HOPE-TOO: Study Conclusions

• The benefits of ramipril were maintained during post-trial follow-up for CV death, stroke, and hospitalization for heart failure

• Additional reductions in MI, revascularization and new-onset diabetes were also observed despite similar rates of ACEI use inthe randomized groups

• The reduction in CV outcomes demonstrated in the HOPE trial is most likely an underestimate of the full effects of long-term ramipril therapy

• Subgroup analyses demonstrate the benefits observed are additiveto those of other life-saving therapies, and extend to all patients with vascular disease, independent of their baseline risk


Major Clinical Outcome Trials of RAAS Manipulation

ACE inhibitionAngiotensin receptor blockade

GISSI-3

ISIS-4AIRESAVESOLVD-PreventionTRACE

CHARM-PreservedOPTIMAALVALIANT

SOLVD-Treat

CHARM-Added

CHARM-AlternativeELITE IIVal-HeFT

CONSENSUS

HOPE

EUROPA

ALLHAT

ANBP2

INVEST

LIFE

ACE Inhibition and Anti- atherosclerotic Effect

(A) Control

Candido R et al. Circulation. 2002;106:246-253.

(B) Diabetic apoE-deficient mice

(C) Diabetic apoE-deficient mice ACE inhibition treated

*Compelling IndicationsHeart failurePost-MIHigh coronary artery disease riskDiabetesChronic kidney diseaseRecurrent stroke prevention

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.

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.

With Compelling Indications

ChobanianChobanian AV et al. AV et al. JAMAJAMA. 2003;289:2560. 2003;289:2560––25722572..

Algorithm for the Treatment of Hypertension

JNC 7

Major Outcomes in High-Risk HypertensivePatients Randomized to Angiotensin-

Converting Enzyme Inhibitor to Calcium Channel Blocker vs Diuretic

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

(ALLHAT)

ALLHAT: Entry CriteriaAge >55 years old

Untreated systolic and/or diastolic hypertension (>140/90 mm Hg but <180/110 mm Hg )At least 1 additional risk factor for CV morbidity, including:

– Type 2 diabetes mellitus– Cigarette smoking – Low HDL cholesterol(<35mg/dl)– LVH

– Old MI or stroke– History of revascularization– Other documented atherosclerosis

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

Years to CHD Event0 1 2 3 4 5 6 7

Cum

ulat

ive

CH

D E

vent

Rat

e

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

0.810.99 (0.91-1.08)L/C0.650.98 (0.90-1.07)A/C

p valueRR (95% CI)

ChlorthalidoneAmlodipineLisinopril

ACE Inhibitor Recommendations for Secondary Prevention

Use in all patients with LVEF < 40%, and those with diabetes or chronic kidney disease indefinitely, unless contraindicated

Consider for all other patients

Among lower risk patients with normal LVEF where cardiovascular risk factors are well controlled and where revascularization has been performed, their use may be considered optional

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


ACE=Angiotensin converting enzyme, LVEF= left ventricular ejection fraction


Hypertension and DyslipidaemiaAre Major Risk Factors for CHD

Kannel W. In: Hypertension: Pathophysiology and Treatment. New York: McGraw-Hill, Inc.; 1977:888-909; Castelli WP.Am J Med. 1984;76:4-12.

Age

40

50

60

70

Framingham Study

0

50

100

150

200

250

300

350

100 120 140 160 180 200

Prob

abili

ty o

f CVD

/100

0

0

20

40

60

80

100

120

140

<204 205-234

235-264

265-294

>295

Pro

babi

lity

of C

VD

/100

0

TC (mg/dL) in menSBP (mm Hg) in men

Additive Effect of Cholesterol and SBP on Risk of CHD Death

Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

142+

125-131

< 182182-202

203-220221-244

Cholesterol quintile(mg/dL)*

SBP quintile (mm Hg)

< 118118-124

132-141

34

21

13

6

23

12

810

6

18

11

96

4

17

88

6

3

Dea

ths

/10,

000

pat

ien

t-ye

ars

245+

14

56

3

12

17

N = 316,099

*To convert to mmol/L multiply by 0.02586

Diuretic Based Regimens

Substantially reduce the risk of strokeThe benefits of diuretic therapy on coronary artery disease were less than than expectedMetabolic side effects of diuretic mitigated the beneficial effect of blood pressure reduction

Major Clinical Outcome Trials of RAAS Manipulation

ACE inhibitionAngiotensin receptor blockade

GISSI-3ISIS-4

AIRESAVESOLVD-PreventionTRACECHARM-Preserved

OPTIMAAL

VALIANT

SOLVD-TreatCHARM-Added

CHARM-Alternative

ELITE II

Val-HeFT

CONSENSUS

HOPEEUROPAPEACE

ALLHATANBP2INVESTLIFE

HOPE: Benefits in All SubgroupsYounger than 65 years as well as 65 years and olderWith/without diabetesWith/without evidence of cardiovascular diseaseWith/without hypertensionWith/without microalbuminuriaWhether or not taking aspirin or other antiplatelet agents, beta blockers, lipid-lowering agents or antihypertensive agents

NEJM 2000; 342: 145-153

Management of The Patients with Hypertension and High ... 16/songsuk...Management of The Patients with Hypertension and High Risk Cardiovascular Disease Songsak Kiatchoosakun, MD.

Documents