HYPERTENSION IN THE ELDERLY

1

• HYPERTENSION IN THE ELDERLY
• AN UPDATE FROM AN OLDER PERSON
• Henry R. Black, M.D.
• Rush University Medical Center
• September 22, 2004

2
(No Transcript)
3
Causes of mortality in the elderly
National Center for Health Statistics (NCHS)
Vital Statistics System, 1998.
4
Age Distribution of Hypertensives in US
Population From NHANES III and the 1990 Census
27
73
23.6
47.4 million hypertensives 26.0 of US population
20.3
19.1
Hypertensives Within Age Group )
14
9.7
9.6
3.7
Age Groups (y)
Franklin SS. J Hypertension. 199917(suppl
5)S29-S36.
5
Age Distribution of Hypertensives in US
Population From NHANES III and the Projected
2020 Census
20
80
70.4 million hypertensives 29.1 of US population
29.2
25.3
Hypertensives Within Age Group ()
13.6
11.5
11.2
6.5
2.7
Age Groups (y)
Franklin SS. J Hypertension. 199917(suppl
5)S29-S36.
6
Characteristics of Hypertension in the Elderly

• INCREASED
• SBP and PP
• Left ventricular mass and wall thickness
• Arterial stiffness
• Calculated total peripheral resistance
• DECREASED
• Cardiac output and heart rate
• Renal blood flow, plasma renin activity, and
  angiotensin II levels
• Arterial compliance and blood volume
• DBP

Messerli FH, et al. Lancet. 19832(8357)983-986.
Weidmann P, et al. Kidney Int. 19758(5)325-333.
Izzo JL, et al. Hypertens. 2000351021-1024.
7
Mean SBP and DBP by Age and Race/Ethnicity for
Men and Women(US Population ?Age 18 Years,
NHANES III)
Pulse pressure
Pulse pressure
Men, Age (y)
Women, Age (y)
Burt VI, et al. Hypertension. 199525305-313.
8
AGE-RELATED CHANGES IN BLOOD PRESSURE
PARAMETERSFranklin SS et al.Circulation 1997
96308
Groups Determined at Index Examination Group 1
SBP lt 120 Group 2 SBP 120-139 Group 3 SBP
140-159 Group 4 SBP gt 160 All subjects
Deaths, MI, CHF excluded
4
3
2
1
Pulse
4
4
3
3
2
2
1
1
Systolic
Diastolic
9
Mortality Risk Increases With Lower Diastolic BP
at Every Level of Systolic BP Meta-analysis
68
Diastolic pressure at baseline (mm Hg)
Control Patients (N7757)
79
83
88
92
2-Year Risk of Death per 100 Patients
180
190
200
210
220
170
160
Systolic BP at Baseline (mm Hg)
Standardized to female sex, mean age (70 y), no
previous CV complications, and nonsmoking. Staess
en et al. Lancet. 2000355865-872.
10
Is There a Better Blood Pressure Index Than SBP
or DBP Alone?
Informativeness as a of Mid Blood Pressure Informativeness as a of Mid Blood Pressure Informativeness as a of Mid Blood Pressure
CHD Stroke
SBP 93 89
DBP 73 83
Pulse Pressure (SBP - DBP) 43 37
Mean Arterial Pressure (1/3 SBP 2/3 DBP) 97 100
Mid Blood Pressure (½ SBP ½ DBP) 100 100
From model ?2 using baseline measurements From model ?2 using baseline measurements From model ?2 using baseline measurements
Lancet 2002 3601903
11
Residual Lifetime Risk of Hypertensionin Women
and Men Aged 65 Years
100
Men
80
60
Risk of hypertension()
Women
40
20
0
0
12
20
2
16
4
6
8
10
14
18
Follow-up (y)
Vasan RS et al. JAMA. 20022871003-1010.
12
Stroke and IHD Mortality vs Usual Systolic BP by
Age
Mortality(Floating absolute risk and 95 CI)
IHD ischemic heart disease.Prospective Studies
Collaboration. Lancet. 20023601903-1913.
13
Prospective Studies Collaboration

• Throughout middle and old age, usual blood
  pressure is strongly and directly related to
  vascular (and overall) mortality, without any
  evidence of a threshold down to at least 115/75
  mm Hg.

Lancet 2002 3601903
14
Prospective Studies Collaboration

• ... other risk factors (such as blood
  cholesterol, diabetes, smoking and weight) were
  not found to have any material influence on the
  proportional differences in vascular mortality
  associated with a given absolute difference in
  usual blood pressure.

Lancet 2002 3601903
15
AWARENESS, TREATMENT,AND CONTROL OF HTN IN
ADULTS
JNC VI. Arch Intern Med 19971572413
16
HYPERTENSION - USA
Treated, uncontrolled
Percent
Controlled
Age
J. Hyper. 17S188, 1999
17
HYPERTENSION IN THE US - NHANES III
UNDERTREATED
13
4
10
18
28
27
Frequency of HBP subtypes In all undertreated
subjects
Age (yrs)
Franklin et al Hyp. 37869, 2001
18
HYPERTENSION IN THE US - NHANES III
UNTREATED
11
17
16
16
20
20
Frequency of HBP subtypes In all untreated
subjects
Age (yrs)
Franklin et al Hyp. 37869, 2001
19
HYPERTENSION AND CV RISK FACTORS 60,343
hypertensive men
Prevalence of Risk Factors
Thomas et al Hypertension, 371256, 2001
20
Progression to Heart Failure from Hypertension
Systolic dysfunction
Smoking Dyslipidemia Diabetes
MI
Heart failure
Death
HTN
Diastolic dysfunction
Obesity Diabetes
LVH
Normal LV Subclinical
Clinical heart LV structure
remodeling LV dysfunction
failure function
Years
Years/months
Pathways of progression
Adapted from Vasan RS et al. Arch Intern Med.
1996,1561789-1796.
21
Hospitalization Rates For CHF(1971-1994)
National Discharge Survey, National Center for
Health Statistics.
22
Heart FailurePrevalence by Age and Gender
9.8
9.7
10
8
Males Females
6.8
6.6
6.2
6
of Population
4
3.4
1.8
2
1.3
0.7
0.5
0.1
0.1
0.1
0.1
0
20-24
25-34
35-44
45-54
55-64
65-74
75
Ages (y)
United State 1988-1994. American Heart
Association. Heart Disease and Stroke Statistics
- 2003 Update.
23
DEMENTIA AND HYPERTENSION

• PREVALENCE
• AGE 70-74 - 2.8
• AGE 90-95 - 38.6
• INCIDENCE
• 10.7/1000 person-years

Harrington et al 361079, 2000
24
DEMENTIA FACTS

• Rate of Alzheimers Disease is projected to
  quadruple in the next 50 years
• If that occurs, 1 in 45 Americans will have AD
• Increase will be primarily in those gt 75 years of
  age
• In 2050, of Americans older than 75 years of
  age will increase from 5.9 now to 11.4
• Once a patient sees an MD for memory problems the
  medial survival is 3.3 years

Kawas and Brookmeyer, NEJM 3441160, 2001
25
DEMENTIA AND HYPERTENSION

• COMPARISON of UNTREATED HYPERTENSIVES
• (n 107) to NORMOTENSIVES (n 116)
• HYPERTENSIVES WERE SLOWER
• FOR ALL 8 TESTS USED
• (number vigilance, reaction times, word and
  picture recognition, spatial memory and memory
  scanning)

Harrington et al Hypertension 361079, 2000
26
DEMENTIA AND HYPERTENSION

• COMPARED UNTREATED HYPERTENSIVES (n 107)
• to NORMOTENSIVES (n 116)
• Hypertensives Normotensives
• (160-179 or 90-99) lt150/90 mm Hg
• Age 76 76
• BP (in mm Hg) 164/99 131/74
• MMSE (score) 29 29

Harrington et al Hypertension 361079, 2000
27
Combined Results of FiveRandomized Trials of
Antihypertensive Treatment in the Elderly
600
T

Treatment
C

Control

Fatal events
494
500
C
438
438
C
C
400
383
362
346
344
T
T
C
T
288
300
Total numbers of individuals affected
279
T
208
200
120
100
78
0
Stroke
CHD
Vascular deaths
All other deaths
34 (6) 2P lt0.0001
(SD) reductionin odds
19 (7) 2P lt0.05
23 (6) 2P lt0.001
7 (8) 2P gt0.5
28
ISH META-ANALYSIS OF OUTCOME TRIALS
n15,6933.8-yr follow-up
1000
Nonfatal events Fatal events Treatment Control
835
800
734
T
656
647
600
C
Total individuals affected (n)
387
373
400
342
327
293
279
100
329
200
244
193
136
100
0
T
C
T
C
T
C
T
C
T
C
Totalmortality130.002
AllCV events 26lt0.001
Non-CVmortality
CHD23lt0.001
Stroke30lt0.0001
odds reduction
2P value
Adapted from Staessen et al. Lancet 2000355865
29
CLINICAL TRIALS IN HTNREDUCTION IN CV
COMPLICATIONS

• Total events () EWPHE STOP I MRC
  SHEP Syst-EUR Syst-China
• Stroke 36 47 25 36 42 38
• CHF 22 52 51 29 58
• All cardiac 20 13 19 25 26 37
• All cardiovascular 29 40 17 32
  31 37
• P?0.05, P?0.001 P?0.003 Plt0.01, Plt 0.004,
  Plt0.09

Modified from Lever and Ramsay. J Hypertens
199513571
30
CLINICAL TRIALS IN HYPERTENSION SYST-EUR STUDY ON
VASCULAR DEMENTIA

• (n 3162, 5622 pt-yrs, avg. f/u - 1.0 yrs, 60
  on nitrendipine alone)
• Placebo Active p Value
• Int. to Treat (per 1000/pt-yrs) 7.7 3.8 lt0.05
• Per protocol (per 1000/pt-yrs) 6.6 2.7 lt 0.03
• Total Incident cases 21 11
• Altzheimers 15 8
• Mixed 4 3
• Vascular 2 0
• BP drop 14/2 22/6
• 1000 pts. Rxd for 5 yrs prevents 19 cases of
  dem. (53 CVD, 27 CVA)

Lancet, 1999
31
SCOPE StudyStudy on COgnition and Prognosis in
the Elderly Cognitive Function, ITT
Relative risk
Number of Events/1000 Patients-Years Number of Events/1000 Patients-Years
Candesartan Control
Significant cognitive decline 13.5 15.2
Dementia 6.8 6.3
Significant cognitive decline and/or dementia 15.3 15.8
1.0
0.5
2.0
Favours candesartan
Favours control
International Society of Hypertension, Prague,
CZ 2002
32
CLINICAL TRIALS IN HYPERTENSION IN THE ELDERLY -
SHEP - ROLE OF LOW K
n 74
n 1989
n 1070
n 734
Chlorthalidone daily dose
Franse et al Hyper. 351025, 2000
33
CLINICAL TRIALS IN HYPERTENSION IN THE ELDERLY -
SHEP - ROLE OF LOW K
Serum K decrease
All differences sig. at p lt 0.001
Franse et al Hyper. 351025, 2000
34
CLINICAL TRIALS IN HYPERTENSION IN THE ELDERLY -
SHEP - ROLE OF LOW K

• HAZARD RATIO - ACTIVE Rx GROUP by SERUM K
• K lt 3.5 mEq/L CVD CHD CVA ACM
• (n 151)
• 1.0 1.0 1.0 1.0
• K gt 3.5 mEq/L
• (n 1951)
• 0.49 0.45 0.28 1.33 (ns)

Franse et al Hyper. 351025, 2000
35
Blood Pressure Control
2.0
1.8
1.7
1.6
1.4
36
Use of Blinded (Step 1) Drug and Numberof
Antihypertensive Drugs Prescribed
On Step 1 Drug
On 1 Drug
Percent
On 2 Drugs
On 3 Drugs
On 4 Drugs
Months of Follow-Up
_at_ 5 years 62 were on gt2 drugs 30 were on 1
drug with BP lt140/90 mm Hg
37
Multiple Logistic Regression Analysis Relative
Odds (95 CI) of BP Control at 36 Months
BP Control Worse
BP Control Better
More () or less (?) likely to be on 2 drugs
Cushman, et al. J Clinical Hypertens 2002
4393-404
38
Logistic Regression Analysis of Relative Odds
(95 CI) of Being On 2 Drugs at 36 Months
Less Likely To Be On 2 Drugs
Cushman, et al. J Clinical Hypertens 2002
4393-404
39
Baseline Characteristics by Age
Age 55-64 65-74 75
N 14,184 13,409 5,764
Black () 38.6 33.5 31.6
Women () 47.5 43.6 53.0
SBP mean (sd) 144.8 (15.6) 146.8 (15.5) 148.6 (15.5)
DBP mean (sd) 86.1 (9.7) 83.2 (9.9) 81.0 (10.3)
Current smokers () 29.5 18.8 10.4
ASCVD () 44.2 54.6 62.7
Diabetes () 36.8 37.3 32.0
40

Blood Pressure at 5 Yearsby Age
Chlorthalidone Amlodipine Lisinopril
SBP mean (sd) lt 65 133.1 (14.8) 134.8 (14.4) 135.0 (18.1)
SBP mean (sd) 65 134.5 (15.4) 134.6 (15.3) 136.5 (17.8)
DBP mean (sd) lt 65 77.5 (9.4) 76.4 (9.7) 77.7 (10.5)
DBP mean (sd) 65 74.0 (9.8) 73.4 (9.8) 73.9 (10.6)
? BP compared with chlorthalidone lt 65 --- 1.7 / -1.1 1.9 / 0.2
? BP compared with chlorthalidone 65 --- 0.1 / -0.7 2.0 / -0.2
P 0.001
05/15/03
41
Blood Pressure at 5 Yearsby Age
Chlorthalidone Amlodipine Lisinopril
SBP - mean (sd) lt65 133.1 (14.8) 134.8 (14.4) 135.0 (18.1)
SBP - mean (sd) 65-74 134.5 (15.1) 134.3 (14.9) 136.2 (17.8)
75 134.5 (16.3) 135.3 (16.2) 137.5 (17.7)
DBP mean (sd) lt65 77.5 (9.4) 76.4 (9.7) 77.7 (10.5)
DBP mean (sd) 65-74 74.6 (9.6) 73.9 (9.4) 74.4 (10.7)
75 72.3 (10.3) 71.8 (11.0) 72.4 (10.0)
? BP compared with chlorthalidone lt65 --- 1.7 / -1.1 1.9 / 0.2
? BP compared with chlorthalidone 65-74 --- -0.2 / -0.7 1.7 / -0.2
75 --- 0.8 / -0.5 2.9 / 0.1
P 0.003
42
AHT Age lt 65
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.99 (0.85 - 1.16)
All-Cause Mortality 0.96 (0.83 - 1.10)
Combined CHD 0.94 (0.84 - 1.05)
Combined CVD 1.03 (0.94 - 1.12)
Stroke 0.93 (0.73 - 1.19)
Heart Failure 1.51 (1.25 - 1.82)
End Stage Renal Disease 1.11 (0.77 - 1.60)
0.50 1 2
Favors Amlodipine Favors
Chlorthalidone
05/14/03
43
AHT Age 65
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.97 (0.88 - 1.08)
All-Cause Mortality 0.96 (0.88 - 1.03)
Combined CHD 1.04 (0.96 - 1.12)
Combined CVD 1.05 (0.99 - 1.12)
Stroke 0.93 (0.81 - 1.08)
Heart Failure 1.33 (1.18 - 1.49)
End Stage Renal Disease 1.12 (0.85 - 1.48)
0.50 1 2
Favors Amlodipine Favors
Chlorthalidone
05/15/03
44
AHT Age 55 - 64
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.99 (0.85 - 1.16)
All-Cause Mortality 0.96 (0.83 - 1.10)
Combined Coronary Heart Disease 0.94 (0.84 - 1.05)
Combined Cardiovascular Disease 1.03 (0.94 - 1.12)
Stroke 0.93 (0.73 - 1.19)
Heart Failure 1.51 (1.25 - 1.82)
End Stage Renal Disease 1.11 (0.77 - 1.60)
0.50 1 2
05/11/03
Favors Amlodipine Favors
Chlorthalidone
45
AHT Age 65 - 74
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.99 (0.87 - 1.12)
All-Cause Mortality 0.98 (0.88 - 1.08)
Combined Coronary Heart Disease 1.05 (0.95 - 1.15)
Combined Cardiovascular Disease 1.06 (0.98 - 1.14)
Stroke 0.98 (0.81 - 1.18)
Heart Failure 1.40 (1.20 - 1.63)
End Stage Renal Disease 1.17 (0.85 - 1.63)
0.50 1 2
Favors Amlodipine Favors
Chlorthalidone
05/11/03
46
AHT Age 75
Amlodipine/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.95 (0.79 - 1.13)
All-Cause Mortality 0.91 (0.81 - 1.03)
Combined Coronary Heart Disease 1.02 (0.88 - 1.18)
Combined Cardiovascular Disease 1.03 (0.92 - 1.14)
Stroke 0.86 (0.68 - 1.09)
Heart Failure 1.22 (1.01 - 1.46)
End Stage Renal Disease 0.98 (0.56 - 1.72)
0.50 1 2
Favors Amlodipine
Favors Chlorthalidone
05/11/03
47
AHT Age lt 65
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.95 (0.81 - 1.12)
All-Cause Mortality 0.93 (0.81 - 1.08)
Combined CHD 0.94 (0.84 - 1.05)
Combined CVD 1.05 (0.97 - 1.15)
Stroke 1.22 (0.97 - 1.52)
Heart Failure 1.23 (1.01 - 1.50)
End Stage Renal Disease 1.26 (0.88 - 1.79)
0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/14/03
48
AHT Age 65
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 1.01 (0.91 - 1.12)
All-Cause Mortality 1.03 (0.95 - 1.12)
Combined CHD 1.11 (1.03 - 1.20)
Combined CVD 1.13 (1.06 - 1.20)
Stroke 1.13 (0.98 - 1.30)
Heart Failure 1.20 (1.06 - 1.35)
End Stage Renal Disease 1.01 (0.76 - 1.36)


0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/15/03
49
AHT Age 55 - 64
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.95 (0.81 - 1.12)
All-Cause Mortality 0.93 (0.81 - 1.08)
Combined Coronary Heart Disease 0.94 (0.84 - 1.05)
Combined Cardiovascular Disease 1.05 (0.97 - 1.15)
Stroke 1.22 (0.97 - 1.52)
Heart Failure 1.23 (1.01 - 1.50)
End Stage Renal Disease 1.26 (0.88 - 1.79)
0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/11/03
50
AHT Age 65 - 74
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 0.98 (0.86 - 1.11)
All-Cause Mortality 1.04 (0.94 - 1.15)
Combined Coronary Heart Disease 1.13 (1.03 - 1.24)
Combined Cardiovascular Disease 1.13 (1.05 - 1.22)
Stroke 1.14 (0.95 - 1.36)
Heart Failure 1.18 (1.01 - 1.39)
End Stage Renal Disease 0.86 (0.60 - 1.24)
0.50 1
2
Favors Lisinopril
Favors Chlorthalidone
05/11/03
51
AHT Age 75
Lisinopril/Chlorthalidone
Relative Risk and 95 Confidence Intervals
Nonfatal MI CHD Death 1.06 (0.89 - 1.26)
All-Cause Mortality 1.00 (0.89 - 1.13)
Combined Coronary Heart Disease 1.06 (0.92 - 1.23)
Combined Cardiovascular Disease 1.12 (1.01 - 1.24)
Stroke 1.10 (0.88 - 1.37)
Heart Failure 1.20 (1.00 - 1.45)
End Stage Renal Disease 1.39 (0.84 - 2.31)
0.50 1 2
Favors Lisinopril Favors
Chlorthalidone
05/11/03
52
Cumulative Event Rates for Stroke by ALLHAT
Treatment Group
RR (95 CI) p value
A/C 0.93 (0.81-1.06) 0.28
L/C 1.15 (1.02-1.30) 0.02
Chlorthalidone Amlodipine Lisinopril
53
Stroke Subgroup Comparisons RR (95 CI)
P .01 for interaction
54
BP Results by Treatment Group
55
VALUE Primary Hypothesis
In hypertensive patients at high cardiovascular
risk, for the same level of blood pressure
control, valsartan will be more effective than
amlodipine in reducing cardiac morbidity and
mortality
Julius S et al. Lancet. June 2004363.
56
VALUE Baseline Characteristics
Variable Valsartan (n 7649) Amlodipine (n 7596)
Women () Age (y) 3240 (42.4) 67.2 8.2 3228 (42.5) 67.3 8.1
BMI (kg/m2) 28.6 5.1 28.7 5.0
HTN previously treated () 7088 (92.7) 6989 (92.0)
SBP (mmHg) 154.5 19.0 154.8 19.0
DBP (mmHg) 87.4 10.9 87.6 10.7
Heart rate (beats/min) 72.3 10.8 72.5 10.7
Race ()
Caucasian 6821 (89.2) 6796 (89.5)
Black 325 (4.3) 314 (4.1)
Oriental 272 (3.6) 261 (3.4)
Other 231 (3.0) 225 (3.0)
Mean SD or of total.
Julius S et al. Lancet. June 2004363.
57
VALUE Qualifying Risk Factorand Disease
Algorithm
Age Range Male Patients Female Patients
50 to 59 yrs At least 3 risk factors or 1 disease At least 2 risk factors and 1 disease or at least 2 diseases
60 to 69 yrs At least 2 risk factors or 1 disease At least 2 risk factors or 1 disease
gt70 yrs At least 1 risk factor or 1 disease At least 1 risk factor or 1 disease
Mann J, Julius S. Blood Press. 19987176183.
58
VALUE Qualifying Risk Factorsand Diseases

• Risk Factors
• Diabetes mellitus
• Cigarette smoking
• Hypercholesterolemia
• Left ventricular hyper-trophy (LVH) without
  strain patterns
• Proteinuria
• Serum creatinine
• 150265 µmol/L

• Diseases
• History of CHD
• Peripheral vascular disease
• Stroke or transient ischemic attack
• LVH with ECG documented strain patterns (ST
  segment depression)

Mann J, Julius S. Blood Press. 19987176183.
59
VALUE Fatal and Non-fatal Stroke
6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.15 95 CI 0.981.35 P 0.08
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7494
7448
7312
7170
6877
7022
6692
6093
3859
1516
6515
Amlodipine
7596
7499
7455
7334
7195
6918
7055
6744
6163
3846
1532
6587
Julius S et al. Lancet. June 2004363.
60
VALUE Outcome and SBP Differencesat Specific
Time Periods Stroke
STROKE
Time Interval
? SBP
(months)
(mmHg)
Odds Ratios and 95 CIs
Overall study
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
1.0
2.0
0.5
0.25
4.0
favors valsartan favors amlodipine
Julius S et al. Lancet. June 2004363.
61
VALUE Systolic Blood Pressure in Study
Sitting SBP by Time and Treatment Group
155
Valsartan (N 7649)
Amlodipine (N 7596)
150
mmHg
145
140
135
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Baseline
Months
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
2.0
mmHg
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004363.
62
VALUE Analysis of Results Based on Immediate
Response

• Outcomes were compared in
• Immediate responders
• patients not on previous treatment, with BP
  response of 10 mmHg SBP at 1 month, OR
• patients on previous treatment, with BP
  baseline at 1 month
• WITH
• Non-immediate responders
• those who failed to meet above criteria

Weber MA et al. Lancet. 2004363204749.
63
VALUE Analysis of Results Based on Immediate
Response
Pooled Treatment Groups
Odds Ratio
Fatal/Non-fatal cardiac events

0.88 (0.790.97)

Fatal/Non-fatal stroke
0.83 (0.710.98)

All-cause death
0.90 (0.810.99)
Myocardial infarction
0.89 (0.761.04)
Heart failure hospitalizations
0.87 (0.751.01)
0.4
0.6
0.8
1.0
1.2
1.4
Immediate responders (n 9336)
Non-immediate responders (n 5663)
Odds Ratio 95 CI
Those not on previous tx SBP ? 10 mmHg at one
month those on previous tx SBP baseline at
one month. P lt 0.05 P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
64
VALUE Analysis of Results Based on BP Control
at 6 Months
Pooled Treatment Groups
Odds Ratio

Fatal/Non-fatal cardiac events
0.75 (0.670.83)

Fatal/Non-fatal stroke
0.55 (0.460.64)

All-cause death
0.79 (0.710.88)
Myocardial infarction
0.86 (0.731.01)

Heart failure hospitalizations
0.64 (0.550.74)
0.4
0.6
0.8
1.0
1.2
1.4
Controlled patients (n 10755)
Non-controlled patients (n 4490)
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
65
VALUE Analysis of Results Based on BP Control
at 6 Months
Patients Treated With Valsartan
Patients Treated With Amlodipine
Odds Ratio
Odds Ratio
Fatal/Non-fatal cardiac events
0.76 (0.660.88)


0.73 (0.630.85)
Fatal/Non-fatal stroke
0.60 (0.480.74)
0.50 (0.390.64)



0.79 (0.690.92)

0.79 (0.690.91)
All-cause death
0.91 (0.711.17)
0.83 (0.661.03)
Myocardial infarction
Heart failure hospitalizations
0.62 (0.500.77)


0.64 (0.520.79)
0.4
0.6
0.8
1.0
1.2
0.4
0.6
0.8
1.0
1.2
Controlled patients (n 5253)
Non-controlled patients (n 2396)
Controlled patients (n 5502)
Non-controlled patients (n 2094)
Hazard Ratio 95 CI
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
66
VALUE Analysis of Results Based on BP Control
at 6 Months
Conclusions Regardless of the class of agent
used, rigorous and prompt BP control provides
powerful cardiovascular benefits these data
validate guidelines recommendations
Weber MA et al. Lancet. 2004363204749.
67
Blood Pressure at Goal (n437) (lt 140 mm Hg/ lt 90
mm Hg)
100
90
Initial visit
80
70
86
AT GOAL
Visit analyzed
60
50
63
59
40
51
30
35
20
28
10
0
SBP at Goal
DBP at Goal
Both at Goal
Singer et al. Hypertension. 2002.
68
Singer et al. Hypertension. 2002.
69
Singer et al. Hypertension. 2002.
70
Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (lt140/90 mmHg)
(lt130/80 mmHg for those with diabetes or chronic
kidney disease)
Initial Drug Choices
71
GOAL OF ANTIHYPERTENSIVE THERAPY

• lt 140 mmHg and lt 90 mmHg
• lt 130 mmHg and lt 80 mmHg (or maybe still lower)
  for diabetics, patients with HF and those with
  CRF
• lt 125 mmHg and lt 75 mmHg for those with gt 1 gram
  of proteinuria
• Goal is not dependent on age, gender or
  co-morbidity

72
JNC VI (7)S.O.C.O.s

• Go For Goal And Dont Settle For Less
• Its not BEYOND the Blood Pressure, IT IS THE
  BLOOD PRESSURE!

S.O.C.O. Single Overriding Communications
Objective
73
ESH - 2003
Blood Pressure (mm Hg) Blood Pressure (mm Hg) Blood Pressure (mm Hg) Blood Pressure (mm Hg) Blood Pressure (mm Hg)
Other risk factors and disease history Normal SBP 120-129 or DBP 80-84 High normal SBP 130-139 or DBP 85-89 Grade 1SBP 140-159 or DBP 90-99 Grade 2SBP 160-179or DBP 100-109 Grade 3SBP ?180 or DBP ?110
No other risk factors Average risk Average risk Low added risk Moderate added risk High added risk
1-2 risk factors Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk
3 or more risk factor or TOD or diabetes Moderate added risk High added risk High added risk High added risk Very high added risk
ACC High added risk Very high added risk Very high added risk Very high added risk Very high added risk
ACC, associated clinical conditions TOD, target
organ damage SBP, systolic blood pressure DBP,
diastolic blood pressure. ESH Guidelines. J
Hypertens. 2003211011-1053.
74
ESH 2003
Access other risk factors,TOD, diabetes, ACC
Initiate lifestyle measures and correctionof
other risk factors or disease
Stratify absolute risk
Moderate
Very high
High
Low
Begin drugtreatmentpromptly
Begin drugtreatmentpromptly
Monitor BPand other risk factors for at least 3
mos
Monitor BPand otherrisk factors for3-12 months
SBP ?140 orDBP ?90 mm Hg
SBP lt140 andDBP lt90 mm Hg
SBP ?140-159 orDBP ?90-99 mm Hg
SBP lt140 andDBP lt90 mm Hg
Begin drugtreatment
Continueto monitor
Consider drugtreatment and elicitpatients
preference
Continueto monitor
ESH Guidelines. J Hypertens. 2003211011-1053.
75
Thresholds for intervention Initial blood
pressure (mmHg)
160-170 100-109
140-159 90-99
gt180/110
130-139 85-89
lt130/85



lt140/90
140-159 90-99
160/100
Target organ damage or cardiovascular
complications or diabetes or 10 year risk of
cardiovascular disease 20
No target organ damage no CV complications
no diabetes 10 year risk of CVD of lt20
Observe, reassess risk of cardiovascular disease
yearly
Treat
Treat
Treat
Reassess yearly
Reassess in 5 years
Unless malignant phase of hypertensive emergency
confirm over 1-2 weeks then treat If
cardiovascular complications, target organ
damage, or diabetes is present, confirm over 3-4
weeks then treat if absent remeasure weekly and
treat if blood pressure persists at these levels
over 4-12 weeks If cardiovascular complications,
target organ damage, or diabetes is present,
confirm over 12 weeks then treat if absent
remeasure monthly and treat if these levels are
maintained and if estimated 10 year
cardiovascular disease risk is 20 Assessed
with risk chart for cardiovascular disease
Williams B et al. BMJ. 2004328634-640.
76
JNC VI (7.5)S.O.C.O.s

• Go For Goal And Dont Settle For Less
• Its not BEYOND the Blood Pressure, IT IS THE
  BLOOD PRESSURE!
• AND ITS ALSO HOW FAST YOU GET TO GOAL

S.O.C.O. Single Overriding Communications
Objective
77
Hypertension in OlderPersons

• More than two-thirds of people over 65 have HTN.
• This population has the lowest rates of BP
  control.
• Treatment, including those who with isolated
  systolic HTN, should follow same principles
  outlined for general care of HTN.
• Lower initial drug doses may be indicated to
  avoid symptoms standard doses and multiple drugs
  will be needed to reach BP targets.

78

• Democracy is the worst form of government except
  for all others that have been tried. W.
  CHURCHILL
• To paraphase, clinical trials are a terrible way
  to decide how to practice medicine. But it is the
  best we have. We have got to find a way to do
  better. H. BLACK, 2004

79
(No Transcript)
80
Development of Hypertension Guidelines the JNCs
and Drug Therapy
Low-dose
HR Black, 2003.
81
Clinical Trials in Hypertension
Should we treat ISH in older persons?
What is the best way to treat HBP?
Should we treat DBP in older persons?
What is the goal of treatment?
Should we treat diastolic HBP?
Can we prevent hypertension?
1960s 1970s 1980s 1990-1995 1996-1999 2000 2001-2
003 2004-2008
TROPHY
HR Black, 2003.
82
Clinical Trials in Patients With Disorders
Related to Hypertension
CVA/ Dementia
LVH
Heart failure/
Post-MI
Renal disease
Dyslipidemia
Diabetes
Atherosclerosis
LIFE
HR Black, 2003.
83
CHD Mortality Risk versus Baseline SBP
34 000 deaths at ages 40-89
8
4
Hazard ratio (floating absolute risk 95CI)
2
Between 130-180 mmHg 25 ? risk for each 20 mmHg
lower baseline SBP
1
120
140
160
180
200
Baseline Systolic blood pressure (mmHg)
Lancet 2002 3601903
84
CHD Mortality Rate in Each Decade of AgeVersus
Usual SBP at the Start of That Decade
34 000 deaths at ages 40 - 89
Lancet 2002 3601903
85
CHD Mortality Rate in All AgesVersus Usual SBP
(About 5 Years Earlier)
34 000 deaths at ages 40-89
Lancet 2002 3601903
86
CHD Mortality Rate in All AgesVersus Usual SBP
(About 5 Years Earlier)
34 000 deaths at ages 40-89
Lancet 2002 3601903
87
CHD Mortality Rate in Each Decade of AgeVersus
Usual DBP at the Start of That Decade
34 000 deaths at ages 40 - 89
Lancet 2002 3601903
88
CHD Mortality Rate in Each Decade of AgeVersus
Usual DBP at the Start of That Decade
34 000 deaths at ages 40 - 89
Lancet 2002 3601903
89
Stroke Mortality Rate in Each Decade of Age
Versus Usual SBP at the Start of That Decade
12 000 deaths at ages 50 - 89
Lancet 2002 3601903
90
RANDOMIZED CLINICAL TRIALS (RCT)

• The RCT was the result of a movement to combat
• authoritarianism in clinical medicine
• unproven claims on therapeutic benefits of new
  substances
• the links of the authoritarian godfathers to
  the companies producing the substances.
• Instead of relying on authority, the objective
  results of the randomized trial would tell us the
  truth.

Vandenbroucke, et al., Lancet 175, 35212, 1998
91
Randomised Trials of Antihypertensive Rx
(n47,653 in 17 trials)
1200 1100 1000 900 800 700 600 500 400 300 200 100
0
1104
Nonfatal events Fatal events
C
964
934
835
T
C
768
C
670
667
T
560
Total numbers of individuals affected
C
T
525
C
470
T
T
234
C
140
T
All other deaths 0sd6
Vascular deaths 21sd4 plt0.001
CHD 16sd4 plt0.001
Stroke 38sd4 plt0.001
reduction in odds sd
T treatment, C control SBP diff 1012 mm Hg,
DBP diff 56 mm Follow-up 5 years
Cutler et al. In Laragh et al, eds.
Hypertension Pathophysiology, Diagnosis, and
Management, vol 1. NY Raven. 1995255
92
Secondary Objectives Subgroups
Pre-specified Age 65 Women African-Americans Diabetic patients Post-hoc Baseline CHD
93
VALUE Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.03 95 CI 0.941.14 P 0.49
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7459
7407
7250
7085
6732
6906
6536
5911
3765
1474
6349
Valsartan
Amlodipine
7596
7469
7424
7267
7117
6772
6955
6576
5959
3725
1474
6391
Julius S et al. Lancet. June 2004363.
94
VALUE Fatal and Non-FatalMyocardial Infarction
7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.19 95 CI 1.02-1.38 P 0.02
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7499
7458
7319
7177
6853
7016
6680
6078
3864
1520
6504
Valsartan
Amlodipine
7596
7497
7458
7332
7205
6905
7065
6727
6141
3840
1532
6562
Julius S et al. Lancet. June 2004363.
95
VALUE Heart Failure
Hospitalization for HF or death from HF
9 8 7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 0.89 95 CI 0.77-1.03 P 0.12
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
6852
7012
6671
6072
3860
1513
6498
Amlodipine
7596
7486
7444
7312
7176
6874
7033
6702
6100
3823
1511
6534
Julius S et al. Lancet. June 2004363.