The Relationship of Systolic and
Diastolic Blood Pressure to
Cardiovascular Disease Risk:
Observational Data
Prevalence of Hypertension in the US
Percent hypertensive
80
66 %
60
51 %
38 %
40
18 %
20
3%
0
72 %
18-29
9%
30-39 40-49 50-59 60-69 70-79
Age
Based on NHANES III (phase 1 and 2)
Hypertension defined as blood pressure 140/90 mmHg or treatment
JNC-VI. Arch Intern Med. 1997;157:2413-2446.
80+
Risk of hypertension (%)
Lifetime Risk of Developing
Hypertension Beginning at Age 65
100
80
Men
Women
60
40
20
0
0
2
4
6
8
10 12
Years
Residual lifetime risk of developing hypertension
among people with blood pressure <140/90 mmHg
Vasan RS, et al. JAMA. 2002; 287:1003-1010.
Copyright 2002, American Medical Association.
14
16 18
20
Ratio (%) of actual to
expected mortality
Mortality According to Blood Pressure
in Men Age 50 to 69
250
200
150
68-82
83-87
88-92
93-97
98-102
100
50
0
158167
148157
138147
128137
98127
Systolic blood pressure (mmHg)
Society of Actuaries. Blood Pressure Study, 1939.
Age-adjusted annual
incidence of CHD per 1000
Blood Pressure and Risk for
Coronary Heart Disease in Men
60
60
50
50
40
40
Age 65-94
30
30
20
20
Age 35-64
10
10
0
0
<120 120- 140- 160- 180+
139 159 179
Systolic blood pressure (mmHg)
Age 65-94
Age 35-64
<75
758595- 105+
84
94
104
Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart
disease (CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
Risk of CHD Death
According to SBP and DBP in MRFIT
Relative risk of
CHD mortality
4
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
1
2
3
(lowest 10%)
<112 112- 118<71
71-
76-
4
5
6
7
121-
125-
129-
132-
79-
81-
84-
86-
CHD=coronary heart disease
He J, et at. Am Heart J. 1999;138:211-219.
Copyright 1999, Mosby Inc.
8
9
10
89-
92-
>98
(highest 10%)
137- 142- >151
Relative risk of
stroke death
Risk of Stroke Death According
to SBP and DBP in MRFIT
9
8
7
6
5
4
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
1
2
3
(lowest 10%)
<112 112- 118<71
71-
76-
4
5
6
7
121-
125-
129-
132-
79-
81-
84-
86-
He J, et at. Am Heart J. 1999;138:211-219.
Copyright 1999, Mosby Inc.
8
9
10
89-
92-
>98
(highest 10%)
137- 142- >151
Age-adjusted annual CVD
event rate per 1000
Isolated Systolic Hypertension
and CVD Risk in Framingham
2.5
100
ISH BP 160/<95 mmHg
BP <140/95 mmHg
80
82
2.4
60
40
20
0
43
33
18
Men
Women
CVD=cardiovascular disease ISH=isolated systolic hypertension
P<0.001 for difference between both men and women with ISH
and blood pressure (BP) <140/95 mmHg
Wilking SV et al. JAMA. 1988;260:3451-3455.
The Relationship of Hypertension
Treatment to CVD Risk Reduction:
Introduction
Hypertension Treatment Effect
Mirrors Observational Data
Incidence of
cardiovascular disease
12
10
8
6
4
2
0
120
140
160
180
Systolic blood pressure
(mmHg)
200
220
Landmark Clinical Trials
Hypertension 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
Relative Risk for Coronary Heart Disease
Odds ratios and
95% confidence intervals
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
0.79
(0.69 to 0.90)
Total
0
He J, et al. Am Heart J. 1999; 138:211-219.
Copyright 1999, Mosby, Inc.
0.5
Active treatment
better than placebo
1
1.5
2
Active treatment
worse than placebo
Relative Risk for Stroke
Odds ratios and
95% confidence intervals
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
0.63
(0.55 to 0.72)
Total
0
He J, et al. Am Heart J. 1999; 138:211-219.
Copyright 1999, Mosby, Inc.
0.5
Active treatment
better than placebo
1
1.5
2
Active treatment
worse than placebo
The Veterans Administration
Cooperative Study
on Antihypertensive Agents
The 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
HCTZ=hydrochlorothiazide
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
The VA Cooperative Study, 1967:
Change in Systolic and Diastolic Blood Pressure
50
Placebo
40
40
30
30
Percent of patients
Percent of patients
50
20
10
0
50
40
Active drugs
30
20
20
10
0
50
40
20
10
0
0
Decrease (-)
28
-76 -60 -44 -28 -12 0 12
(+) Increase
Change in Systolic BP (mmHg)
Active drugs
30
10
-76 -60 -44 -28 -12 0 12
Placebo
Decrease (-)
28
(+) Increase
Change in Diastolic BP (mmHg)
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
Copyright ©1967, American Medical Association.
The VA Cooperative Study, 1967:
Assessable Morbid/Fatal Events
Placebo
n=70
Active Rx*
n=73
12
0
Stroke
4
1
Coronary event
2
0
CHF
2
0
Renal damage
2
0
Deaths
4
0
Accelerated hypertension
*P<0.001 active drug therapy vs placebo
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
The VA Cooperative Study, 1967:
Conclusions
 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, 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.
The VA Cooperative Study, 1970:
Assessable Morbid/Fatal Events
Placebo
n=194
Active Rx*
n=186
4
0
Stroke
20
5
Total coronary event
13
11
Fatal coronary event
11
6
Congestive heart failure
11
0
3
0
19
8
Accelerated hypertension
Renal damage
Deaths
*P<0.001 active drug therapy vs placebo
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
The VA Cooperative Study, 1970:
Conclusions
 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
High Blood Pressure in the Elderly, 1985
The European Working Party on High
Blood Pressure in the Elderly, 1985
Cohort
Age
Eligibility
Design
840; 30% men
> 60 yrs old; mean 72 yrs old
Systolic BP 150239 mmHg;
diastolic BP 90119 mmHg
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.
Survival free of event (%)
EWPHE Cardiovascular Mortality
On-Treatment Analysis
100
P=0.023
Active (n=416)
90
80
70
0
Placebo (n=424)
1
2
3
4
Year of follow-up
5
EWPHE=European Working Party on High Blood Pressure in the Elderly
Amery A, et al. Lancet. 1985;1:1349-1354.
Reprinted with permission from Elsevier Science.
6
7
EWPHE
Conclusions
• 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
EWPHE=European Working Party on High Blood Pressure in the Elderly
Amery A, et al. Lancet. 1985;1:1349-1354.
The Hypertension Detection
and Follow-up Program, 1979
The Hypertension Detection
and Follow-up Program, 1979
Cohort
Age
Eligibility
Design
10,940; 54% men; 44% black
3069 yrs old; mean 50.8 yrs old
Diastolic BP  90 mmHg
Stepped Care vs Referred Care
Therapy
Chlorthalidone (reserpine, methyldopa)
Duration
5 years
BP change 5 mmHg (Stepped Care vs Referred Care)
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
HDFP Mortality Rates
Cumulative mortality (%)
Entire Cohort
*P<0.01
8
*
6
Referred Care
(n=5,456)
4
Stepped Care
2
0
(n=5,485)
0
1
2
3
4
Year of follow-up
HDFP=Hypertension Detection and Follow-up Program
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
5
6
HDFP Mortality Rates
Cumulative mortality (%)
Diastolic BP 90104 mmHg
*P<0.01
8
*
6
Referred Care
4
(n=3,822)
Stepped Care
2
0
(n=3,903)
0
BP=blood pressure
1
2
3
4
Year of follow-up
HDFP=Hypertension Detection and Follow-up Program
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
5
6
HDFP
Conclusions
• 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 90104
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 (9094 and 9599
mmHg) reduced mortality
HDFP=Hypertension Detection and Follow-up Program
HDFP Cooperative Group. JAMA. 1979;242:2562-2571.
The Systolic Hypertension
in the Elderly Program, 1991
The Systolic Hypertension in
the Elderly Program, 1991
Cohort
4,736; 43% men
Age
 60 yrs old; mean 71.6 yrs old
Eligibility
Systolic BP 160219 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
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP
Change in Blood Pressure
Diastolic BP
Change in BP (mmHg)
Systolic BP
80
180
170
Placebo (n=2,371)
75
Placebo (n=2,371)
160
70
150
Active Rx (n=2,365)
Active Rx (n=2,365)
65
140
0
1
2 3
Years
4
5
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Copyright ©1991, American Medical Association.
0
1
2 3
Years
BP=blood pressure
4
5
Blood pressure (mmHg)
SHEP
Average Blood Pressure During Follow-up
200
185
170
155
140
125
110
95
80
65
50
0
0
12
24
36
Months of follow-up
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Copyright ©1991, American Medical Association.
48
60
Cumulative stroke rate
per 100 persons
SHEP
Cumulative Stroke Rate
10
9
8
7
6
5
4
3
2
1
0
P=0.0003
Placebo
(n=2,371)
Active Rx
(n=2,365)
0
12
24
36
48
Months of follow-up
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Copyright ©1991, American Medical Association.
60
72
Relative risk (95% CI)
SHEP
Cardiovascular Disease Endpoints
Active Therapy vs. Placebo
1.60
1.40
1.20
1.00
0.80
0.60
0.87
0.63
0.68
0.75
0.46
0.40
0.20
Stroke
CHD
CHF
CVD
Death
CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP
Conclusions
 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=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
The Systolic Hypertension
in Europe (Syst-Eur) Trial, 1997
The Systolic Hypertension
in Europe Trial, 1997
Cohort
Age
Eligibility
Design
4,695; 67% women
 60 yrs old
Systolic BP 160–219 mmHg and
diastolic BP <95 mmHg
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.
Syst-Eur Mean Sitting
Systolic Blood Pressure
Placebo (n=2,297)
Systolic BP (mmHg)
180
Active treatment (n=2,398)
170
160
150
P<0.001
0
1
2
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
3
4
Syst-Eur Mean Sitting
Diastolic Blood Pressure
Diastolic BP (mmHg)
85
P<0.001
80
Placebo (n=2,297)
Active treatment (n=2,398)
75
0
1
2
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
3
4
Events per 100 patients
Syst-Eur Primary Endpoint
Fatal and Nonfatal Stroke
P=0.003
Placebo (n=2,297)
6
Active treatment (n=2,398)
5
4
3
2
1
0
0
1
2
3
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
4
Percentage relative
risk reduction (95% CI)
Syst-Eur
Cardiovascular Disease Endpoints
20
Active therapy vs. placebo
0
14%
-20
-40
-60
-80
30%
29%
31%
P<0.001
42%
P=0.003
Stroke
MI
CHF
All CVD
Death
MI=myocardial infarction; CHF=congestive heart failure; CVD=cardiovascular disease
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Syst-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.
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
The Australian National
Blood Pressure (ANBP) Study, 1980
The Australian National
Blood Pressure Study, 1980
Cohort
Age
Eligibility
Design
3,427; 80% men
30–69 yrs old
Diastolic BP 95–109 mmHg
Single blind; placebo control
Therapy
Chlorothiazide (methyldopa, beta blocker)
Duration
4 yrs
BP
difference
-6 mmHg
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian Study
Mean Diastolic Blood Pressure
Diastolic blood
pressure (mmHg)
104
Placebo
100
Active
96
92
88
84
80
At Screening
During Trial
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian Study
Incidence of Trial Endpoints (TEP)*
Intention-to-treat
Placebo (n=1,706)
Active (n=1,721)
No.
Rate
No.
Rate
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†
Total Fatal TEP
*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 Study
Intention-to-Treat Trial Endpoints
No. of events
Placebo
n=1,706
Active
n=1,721
Fatal
11
5
Nonfatal myocardial infarction
22
28
Nonfatal other
76
65
6
3
16
10
9
4
Other fatal
18
17
Other nonfatal
10
6
Ischemic heart disease
Cerebrovascular events
Fatal
Nonfatal
Hemorrhage or thrombosis
Transient cerebral ischemic attacks
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian Study
On-Treatment Trial Endpoints (TEP)
Number of trial endpoints
140
120
Active (n=1,721)
All TEP
P<0.01
Placebo (n=1,706)
100
80
60
All Fatal TEP
40
P<0.05
20
0
400
600
1200
Days in trial
The Australian Study Committee. Lancet. 1980;1:1261-1267.
Reprinted with permission from Elsevier Science.
1600
2000
The Australian Study
Conclusions
• 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.