the relationship of systolic and diastolic blood pressure to cardiovascular disease risk:...
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The Relationship of Systolic and The Relationship of Systolic and Diastolic Blood Pressure to Diastolic Blood Pressure to
Cardiovascular Disease Risk: Cardiovascular Disease Risk: Observational DataObservational Data
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Prevalence of Hypertension in the USPrevalence of Hypertension in the USP
erc
en
t h
yp
ert
en
siv
e
18-29
Based on NHANES III (phase 1 and 2)Hypertension defined as blood pressure 140/90 mmHg or treatment
30-39 40-49 50-59 60-69 70-79 80+
Age
3 %9 %
18 %
38 %
51 %
66 %72 %
JNC-VI. Arch Intern Med. 1997;157:2413-2446.
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Ris
k o
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yp
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%)
Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg
Years
Lifetime Risk of Developing Lifetime Risk of Developing Hypertension Beginning at Age 65Hypertension Beginning at Age 65
Men Women
Vasan RS, et al. JAMA. 2002; 287:1003-1010.Copyright 2002, American Medical Association.
Mortality According to Blood Pressure Mortality According to Blood Pressure in Men Age 50 to 69in Men Age 50 to 69
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100
150
200
250
158-167
148-157
138-147
128-137
98-127
98-10293-97
88-9283-87
68-82
Society of Actuaries. Blood Pressure Study, 1939.
Rati
o (
%)
of
actu
al to
exp
ecte
d m
ort
ality
Systolic blood pressure (mmHg)
Dia
stol
ic b
lood
pres
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(mm
Hg)
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<120 120-139
140-159
160-179
180+0
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<75 75-84
85-94
95-104
105+
Ag
e-a
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HD
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Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baseline
Systolic blood pressure (mmHg)
Blood Pressure and Risk for Blood Pressure and Risk for Coronary Heart Disease in MenCoronary Heart Disease in Men
Diastolic blood pressure (mmHg)
Age 65-94Age 65-94
Age 35-64Age 35-64
Age 65-94Age 65-94
Age 35-64Age 35-64
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
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Rela
tive r
isk o
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HD
mort
ality
He J, et at. Am Heart J. 1999;138:211-219.Copyright 1999, Mosby Inc.
<112
<71
Risk of CHD Death Risk of CHD Death According to SBP and DBP in MRFITAccording to SBP and DBP in MRFIT
1 2 3 4 5 6 7 8 9 10Decile
112-
71-
118-
76-
121-
79-
125-
81-
129-
84-
132-
86-
137-
89-
142-
92-
>151
>98
(lowest 10%) (highest 10%)SBP (mmHg)
DBP (mmHg)
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
CHD=coronary heart disease
0123456789
Rela
tive r
isk o
f str
oke d
eath
<112
<71
Risk of Stroke Death According Risk of Stroke Death According to SBP and DBP in MRFITto SBP and DBP in MRFIT
1 2 3 4 5 6 7 8 9 10Decile
112-
71-
118-
76-
121-
79-
125-
81-
129-
84-
132-
86-
137-
89-
142-
92-
>151
>98
(lowest 10%) (highest 10%)SBP (mmHg)
DBP (mmHg)
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
He J, et at. Am Heart J. 1999;138:211-219.Copyright 1999, Mosby Inc.
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Ag
e-a
dju
ste
d a
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ual C
VD
even
t ra
te p
er
1000
Wilking SV et al. JAMA. 1988;260:3451-3455.
Men Women
Isolated Systolic Hypertension Isolated Systolic Hypertension and CVD Risk in Framinghamand CVD Risk in Framingham
ISH BP 160/<95 mmHg
BP <140/95 mmHg
82
4333
2.4
18
2.5
CVD=cardiovascular disease ISH=isolated systolic hypertensionP<0.001 for difference between both men and women with ISH and blood pressure (BP) <140/95 mmHg
The Relationship of Hypertension The Relationship of Hypertension Treatment to CVD Risk Reduction:Treatment to CVD Risk Reduction:
IntroductionIntroduction
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Incid
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f card
iovascu
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dis
ease
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Hypertension Treatment Effect Hypertension Treatment Effect Mirrors Observational DataMirrors Observational Data
140 160 180 200 220
Observational D
ata
Observational D
ata
Treatment E
ffect
Systolic blood pressure (mmHg)
Landmark Clinical TrialsLandmark Clinical TrialsHypertension Treatment and Cardiovascular Disease OutcomesHypertension Treatment and Cardiovascular Disease Outcomes
1967 – VA Cooperative Study on DBP 115-129
1970 – VA Cooperative Study on DBP 90-114
1979 – HDFP
1980 – Australian Trial, Oslo Trial
1985 – MRC I, EWPHE
1991 – SHEP, STOP-Hypertension
1992 – MRC II in the elderly
1997 – Syst-Eur
2002 – LIFE
2002 – ALLHAT
Veterans Administration, 1967
Veterans Administration, 1970
Hypertension Stroke Study, 1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study, 1991
MRC Study, 1992
Syst-Eur Study, 1997
Total
Relative Risk for Coronary Heart DiseaseRelative Risk for Coronary Heart DiseaseOdds ratios and
95% confidence intervals
0 0.5 1 1.5 2
0.79(0.69 to 0.90)
He J, et al. Am Heart J. 1999; 138:211-219.Copyright 1999, Mosby, Inc.
Active treatment better than placebo
Active treatment worse than placebo
Veterans Administration, 1967
Veterans Administration, 1970
Hypertension Stroke Study, 1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study, 1991
MRC Study, 1992
Syst-Eur Study, 1997
Total
Relative Risk for Stroke Relative Risk for Stroke
0 0.5 1 1.5 2
0.63(0.55 to 0.72)
Odds ratios and95% confidence intervals
Active treatment better than placebo
Active treatment worse than placeboHe J, et al. Am Heart J. 1999; 138:211-219.
Copyright 1999, Mosby, Inc.
The Veterans Administration The Veterans Administration Cooperative Study Cooperative Study
on Antihypertensive Agentson Antihypertensive Agents
The VA Cooperative Study, 1967The VA Cooperative Study, 1967
Cohort 143 men
Mean age 51 years
Eligibility Diastolic BP 115-129 mmHg
Design Double blind; placebo control
Therapy HCTZ, reserpine, hydralazine
Duration 1.5 years
BP change -43/30 mmHg
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
HCTZ=hydrochlorothiazide
-12 12
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The VA Cooperative Study, 1967: The VA Cooperative Study, 1967: Change in Systolic and Diastolic Blood PressureChange in Systolic and Diastolic Blood Pressure
Change in Systolic BP (mmHg)
Perc
en
t of
pati
en
ts
Perc
en
t of
pati
en
ts
Change in Diastolic BP (mmHg)
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10
20
30
40
500
10
20
30
40
50
0
10
20
30
40
50
-76 -60 -44 -28 0 28
Decrease (-) (+) Increase
Active drugs
Placebo
Active drugs
Placebo
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.Copyright ©1967, American Medical Association.
-12 12-76 -60 -44 -28 0 28
Decrease (-) (+) Increase
The VA Cooperative Study, 1967:The VA Cooperative Study, 1967:Assessable Morbid/Fatal EventsAssessable Morbid/Fatal Events
Placebon=70
Active Rx*n=73
Accelerated hypertension
12 0
Stroke 4 1
Coronary event 2 0
CHF 2 0
Renal damage 2 0
Deaths 4 0
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
*P<0.001 active drug therapy vs placebo
The VA Cooperative Study, 1967:The VA Cooperative Study, 1967:ConclusionsConclusions
The actively treated group experienced a reduction in multiple hypertension-related endpoints
21 morbid/fatal events on placebo
1 morbid/fatal event on active therapy
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
The VA Cooperative Study, 1970The VA Cooperative Study, 1970
Cohort 380 men
Mean age 50 years
Eligibility Diastolic BP 90-114 mmHg
Design Double blind; placebo control
Therapy HCTZ, reserpine, hydralazine
Duration 5.5 years (mean=3.8 yrs)
BP change Diastolic BP -19 mmHg
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
PlaceboPlacebon=194n=194
Active Rx*Active Rx*n=186 n=186
Accelerated hypertension
4 0
Stroke 20 5
Total coronary event 13 11
Fatal coronary event 11 6
Congestive heart failure 11 0
Renal damage 3 0
Deaths 19 8
The VA Cooperative Study, 1970:The VA Cooperative Study, 1970:Assessable Morbid/Fatal EventsAssessable Morbid/Fatal Events
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
*P<0.001 active drug therapy vs placebo
The VA Cooperative Study, 1970:The VA Cooperative Study, 1970:ConclusionsConclusions
Active treatment reduced fatal and nonfatal endpoints
A subsequent analysis revealed that benefits were statistically significant only for those with baseline diastolic blood pressure 105-114 mmHg
VA Cooperative Study Group. Circulation. 1972; 45 (5):991-1004.VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
The European Working Party on The European Working Party on High Blood Pressure in the Elderly, 1985High Blood Pressure in the Elderly, 1985
The European Working Party on High The European Working Party on High Blood Pressure in the Elderly, 1985Blood Pressure in the Elderly, 1985
Cohort 840; 30% men
Age > 60 yrs old; mean 72 yrs old
EligibilitySystolic BP 150239 mmHg; diastolic BP 90119 mmHg
Design Double blind; placebo control
Therapy HCTZ, triamterene
Duration 4.7 years
BP change -21/10 mmHg at 5 years
Amery A, et al. Lancet. 1985;1:1349-1354.
70
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90
100
Su
rviv
al fr
ee o
f even
t (%
)
Year of follow-up
EWPHE Cardiovascular Mortality EWPHE Cardiovascular Mortality On-Treatment AnalysisOn-Treatment Analysis
Active (n=416)
Placebo (n=424)
P=0.023
0 1 3 62 4 5 7
Amery A, et al. Lancet. 1985;1:1349-1354.Reprinted with permission from Elsevier Science.
EWPHE=European Working Party on High Blood Pressure in the Elderly
EWPHEEWPHEConclusionsConclusions
• Active treatment reduced cardiovascular (CV) mortality, largely due to a reduction in cardiac mortality
• Older patients (>60 yrs old) with combined systolic and diastolic hypertension who received active therapy experienced 29 fewer CV events and 14 fewer CV deaths per 1,000 patient-years of treatment
Amery A, et al. Lancet. 1985;1:1349-1354.
EWPHE=European Working Party on High Blood Pressure in the Elderly
The Hypertension Detection The Hypertension Detection and Follow-up Program, 1979and Follow-up Program, 1979
The Hypertension Detection The Hypertension Detection and Follow-up Program, 1979and Follow-up Program, 1979
Cohort 10,940; 54% men; 44% black
Age 3069 yrs old; mean 50.8 yrs old
Eligibility Diastolic BP 90 mmHg
Design Stepped Care vs Referred Care
Therapy Chlorthalidone (reserpine, methyldopa)
Duration 5 years
BP change5 mmHg (Stepped Care vs Referred Care)
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
0
2
4
6
8
Cu
mu
lati
ve m
ort
ality
(%
)
0 1 3 6Year of follow-up
HDFP Mortality RatesHDFP Mortality RatesEntire Cohort
2 4 5
Referred Care
Stepped Care
HDFP=Hypertension Detection and Follow-up Program
*P<0.01
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
(n=5,456)
(n=5,485)
*
0
2
4
6
8
0 1 3 62 4 5
Cu
mu
lati
ve m
ort
ality
(%
)HDFP Mortality RatesHDFP Mortality Rates
Diastolic BP 90104 mmHg
Referred Care
Stepped Care
HDFP=Hypertension Detection and Follow-up Program
Year of follow-up
*P<0.01
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
(n=3,822)
(n=3,903)
*
BP=blood pressure
HDFPHDFPConclusionsConclusions
• Overall, stepped care (SC) compared to referred care (RC) reduced total mortality by 17% (6.4 vs. 7.7%; P<0.01)
• In patients with baseline diastolic blood pressure 90104 mmHg (n=7,725), mortality was reduced by 20% with SC vs. RC (5.9% vs. 7.4%; P<0.01)
• Aggressive treatment of SC patients with the lowest baseline diastolic blood pressures (9094 and 9599 mmHg) reduced mortality
HDFP=Hypertension Detection and Follow-up Program
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
The Systolic Hypertension The Systolic Hypertension in the Elderly Program, 1991in the Elderly Program, 1991
The Systolic Hypertension in The Systolic Hypertension in the Elderly Program, 1991the Elderly Program, 1991
SHEP Research Group. JAMA. 1991;265:3255-3264.
Cohort 4,736; 43% men
Age 60 yrs old; mean 71.6 yrs old
EligibilitySystolic BP 160219 mmHg and Diastolic BP <90 mmHg
Design Double blind; placebo control
Therapy Chlorthalidone (atenolol as step 2)
Duration 4.5 years
BP change Systolic BP –12 mmHg
BP=blood pressure
65
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80
140
150
160
170
180
Ch
an
ge in
BP
(m
mH
g)
Years
SHEPSHEPChange in Blood PressureChange in Blood Pressure
Placebo (n=2,371)
Active Rx (n=2,365)
Years
0 1 2 3 4 5 0 1 2 3 4 5
Systolic BPSystolic BP Diastolic BPDiastolic BP
SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright ©1991, American Medical Association.
BP=blood pressureSHEP=Systolic Hypertension in the Elderly Program
Placebo (n=2,371)
Active Rx (n=2,365)
Blo
od
pre
ssu
re (
mm
Hg
)
0 12 36 60Months of follow-up
SHEPSHEPAverage Blood Pressure During Follow-upAverage Blood Pressure During Follow-up
24 4850
65
80
95
110
125
140
155
170
185
200
0
SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright ©1991, American Medical Association.
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10
Cu
mu
lati
ve s
troke r
ate
p
er
100 p
ers
on
s
0 12 36 60Months of follow-up
SHEPSHEPCumulative Stroke RateCumulative Stroke Rate
24 48 72
P=0.0003
Placebo(n=2,371)
Active Rx (n=2,365)
SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright ©1991, American Medical Association.
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
Rela
tive r
isk (
95%
CI)
Stroke CHD
Active Therapy vs. Placebo
CHF Death
0.630.63
0.460.46
0.680.68
0.870.87
CVD
0.750.75
SHEPSHEPCardiovascular Disease EndpointsCardiovascular Disease Endpoints
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP=Systolic Hypertension in the Elderly Program
CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease
SHEPSHEPConclusionsConclusions
SHEP was the first clinical trial to demonstrate that reduction of blood pressure in patients with isolated systolic hypertension reduced cardiovascular (CV) mortality
The relative risk of stroke was reduced by 36% with therapy compared to placebo (P=0.0003)
The 5-year absolute benefits were a reduction in 30 strokes and 55 major CV disease events per 1,000 persons
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP=Systolic Hypertension in the Elderly Program
The Systolic Hypertension The Systolic Hypertension in Europe (Syst-Eur) Trial, 1997in Europe (Syst-Eur) Trial, 1997
The The SystSystolic Hypertension olic Hypertension in in EurEurope Trial, 1997ope Trial, 1997
Cohort 4,695; 67% women
Age 60 yrs old
EligibilitySystolic BP 160–219 mmHg and diastolic BP <95 mmHg
Design Double blind; placebo control
Therapy Nitrendipine (enalapril, HCTZ as Step 2)
Duration Median 2 yrs (1-97 months)
BP difference
-10/5 mmHg
Staessen JA, et al. Lancet. 1997;350:757-764.
150
160
170
180
Systo
lic B
P (
mm
Hg
)Syst-Eur Mean Sitting Syst-Eur Mean Sitting Systolic Blood PressureSystolic Blood Pressure
0
Placebo (n=2,297)
Active treatment (n=2,398)
1 2 3 4Years since randomization
Staessen JA, et al. Lancet. 1997;350:757-764.Reprinted with permission from Elsevier Science.
Syst-Eur=Systolic Hypertension in Europe Trial
P<0.001
75
80
85
Syst-Eur Mean Sitting Syst-Eur Mean Sitting Diastolic Blood PressureDiastolic Blood Pressure
0 1 2 3 4
Dia
sto
lic B
P (
mm
Hg
)
Placebo (n=2,297)
Active treatment (n=2,398)
P<0.001
Years since randomization
Staessen JA, et al. Lancet. 1997;350:757-764.Reprinted with permission from Elsevier Science.
Syst-Eur=Systolic Hypertension in Europe Trial
0
1
2
3
4
5
6
Even
ts p
er
100 p
ati
en
tsSyst-Eur Primary EndpointSyst-Eur Primary EndpointFatal and Nonfatal StrokeFatal and Nonfatal Stroke
Placebo (n=2,297)
Active treatment (n=2,398)
0 1 3 42
P=0.003
Years since randomization
Staessen JA, et al. Lancet. 1997;350:757-764.Reprinted with permission from Elsevier Science.
Syst-Eur=Systolic Hypertension in Europe Trial
-80
-60
-40
-20
0
20
Perc
en
tag
e r
ela
tive
risk r
ed
ucti
on
(95%
CI)
Stroke MI
Active therapy vs. placebo
CHF Death
42%42%P=0.003
29%29% 31%31%P<0.001
14%14%
All CVD
30%30%
Syst-EurSyst-EurCardiovascular Disease EndpointsCardiovascular Disease Endpoints
Staessen JA, et al. Lancet. 1997;350:757-764.
MI=myocardial infarction; CHF=congestive heart failure; CVD=cardiovascular disease
Syst-Eur=Systolic Hypertension in Europe Trial
Syst-Eur ConclusionsSyst-Eur Conclusions
• Older men and women with isolated systolic hypertension who received active treatment with a dihydropyridine calcium channel blocker experienced fewer strokes and cardiovascular disease (CVD) events than those receiving placebo.
• Treatment of 1,000 patients for 5 years with this type of regimen could prevent 29 strokes or 53 major CVD endpoints.
Staessen JA, et al. Lancet. 1997;350:757-764.
Syst-Eur=Systolic Hypertension in Europe Trial
The Australian National The Australian National Blood Pressure (ANBP) Study, 1980Blood Pressure (ANBP) Study, 1980
The Australian National The Australian National Blood Pressure Study, 1980Blood Pressure Study, 1980
The Australian Study Committee. Lancet. 1980;1:1261-1267.
Cohort 3,427; 80% men
Age 30–69 yrs old
Eligibility Diastolic BP 95–109 mmHg
Design Single blind; placebo control
TherapyChlorothiazide (methyldopa, beta blocker)
Duration 4 yrs
BP difference
-6 mmHg
80
84
88
92
96
100
104
At Screening During Trial
Placebo Active
The Australian Study The Australian Study Mean Diastolic Blood PressureMean Diastolic Blood Pressure
Dia
sto
lic b
lood
p
ressu
re (
mm
Hg
)
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian Study The Australian Study Incidence of Trial Endpoints (TEP)*Incidence of Trial Endpoints (TEP)*
Intention-to-treat
Placebo (n=1,706) Active (n=1,721)
No. Rate No. Rate
Total Fatal TEP 35 5.1 25 3.6
Cardiovascular 18 2.6 8 1.1‡
Non-cardiovascular 17 2.5 17 2.4
Non-fatal TEP 133 19.4 113 16.2
All TEP 168 24.5 138 19.7†
*Rates per 1,000 person-years exposure to risk.†P<0.05 ‡P<0.025
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian StudyThe Australian Study Intention-to-Treat Trial Endpoints Intention-to-Treat Trial Endpoints
No. of events
Placebon=1,706
Activen=1,721Ischemic heart disease
Fatal 11 5
Nonfatal myocardial infarction 22 28
Nonfatal other 76 65
Cerebrovascular events
Fatal 6 3
Nonfatal
Hemorrhage or thrombosis 16 10
Transient cerebral ischemic attacks 9 4
Other fatal 18 17
Other nonfatal 10 6
The Australian Study Committee. Lancet. 1980;1:1261-1267.
0
20
40
60
80
100
120
140
The Australian Study The Australian Study On-Treatment Trial Endpoints (TEP)On-Treatment Trial Endpoints (TEP)
Nu
mb
er
of
tria
l en
dp
oin
ts
Days in trial200016001200600400
All TEPP<0.01
All Fatal TEPP<0.05
Active (n=1,721)
Placebo (n=1,706)
The Australian Study Committee. Lancet. 1980;1:1261-1267.Reprinted with permission from Elsevier Science.
The Australian Study The Australian Study ConclusionsConclusions
• The actively treated compared to placebo group experienced 30 fewer trial endpoints endpoints (P<0.05)
• There was a significant reduction in mortality in the actively treated group, mostly due to a reduction in death from cardiovascular disease (P<0.025)
The Australian Study Committee. Lancet. 1980;1:1261-1267.