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Management of The Patients with Hypertension and High Risk
Cardiovascular Disease
Songsak Kiatchoosakun, MD.Cardiology, MedicineKhon Kaen University
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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
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Hypertension
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*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)*
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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
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Establishing blood pressure levelsIdentifying secondary causes of hypertensionEvaluating the overall cardiovascular risk
Other risk factorsTarget organ damageConcomitant diseases
Assessment of Patient with HT
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Blood Pressure Measurement
Sir, your blood pressure is OK.
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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)
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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
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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
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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
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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)
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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.
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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
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Diagnostic Evaluation
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Blood Test
• FBS• Lipid panel• Renal function• Electrolyte
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Waist Circumference
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Electrocardiography
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Proteinuria
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Echocardiography: LV Hypertrophy
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Carotid Plaque
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Total Cardiovascular Risk
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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
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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
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Treatment Strategies
Lifestyle changes
Smoking cessation
Moderation of alcohol consumption
Sodium restriction
Other dietary changes
Weight reduction
Physical exercise
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Antihypertensive Therapy
Five major classesDiureticsBeta-blockerACE inhibitionAngiotensin receptor antagonistCalcium antagonist
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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.
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Clinical Research Questions in Hypertension
Is blood pressure lowering beneficial ?
Does it matter how elevated bloodpressure is lowered ?
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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)
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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
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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
Main HOPE study ends
28832837
28032763
27042672
26002587
23922431
18131853
12691324
10211092
New-onsetdiabetes
(% HOPE-TOO patients)
PlaceboRamipril
n
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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)
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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
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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
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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
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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.
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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
Dahlöf B et al Lancet 2002;359:995-1003.
Number at risk
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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
Dahlöf B et al Lancet 2002;359:995-1003.
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 %
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LIFE:Myocardial Infarction and CV Mortality
Cardiovascular mortality
Dahlöf B et al Lancet 2002;359:995-1003.
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
Losartan 4605 4525 4478 4430 4367 4307 4258 4196 4139 3999 1953 936Atenolol 4588 4517 4466 4415 4364 4302 4243 4192 4134 3975 1953 937
0 6 12 18 24 30 36 42 48 54 60 660
1
2
3
4
5
6
7
8
Losartan 4605 4563 4532 4496 4448 4410 4373 4327 4284 4152 2005 976Atenolol 4588 4453 4513 4474 4442 4388 4341 4299 4252 4107 2006 965
Study Month
Study Month
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Results from ASCOTResults from ASCOT--BPLA:BPLA:AAnglonglo--SScandinavian candinavian CCardiac ardiac
OOutcomes utcomes TTrialrial––BBlood lood PPressure ressure LLowering owering AArmrm
VBWG
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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
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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
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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
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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
Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.
*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn
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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
Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.
VBWG
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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
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New Onset Diabetes: Impact of Blood Pressure Lowering Drugs
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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
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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
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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
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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
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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
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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
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Thank You for Your Attention
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VALUEValsartan
Antihypertensive Long-Term Use
Evaluation
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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.
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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
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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
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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) (
%)
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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
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Possible Combinations Between Some Classes of Antihypertensive Drugs
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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
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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
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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
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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
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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/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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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
HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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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/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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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/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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HOPE-TOO: Additional Reduction in MI
HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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
Main HOPE study ends
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HOPE-TOO: Sustained Reduction in Stroke
HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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
Main HOPE study ends
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HOPE-TOO: Sustained Reduction in CV Death
HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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
Main HOPE study ends
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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
HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.
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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
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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
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*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
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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)
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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.
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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
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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
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
ACE=Angiotensin converting enzyme, LVEF= left ventricular ejection fraction
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
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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
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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
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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
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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
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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