HYPERTENSION MANAGEMENT AND STROKE PREVENTION ...

HYPERTENSION MANAGEMENT
AND STROKE PREVENTION:
ALLHAT AND JNC-7
Jeffrey L. Probstfield, MD, FACP. FACC
Professor of Medicine and Epidemiology
University of Washington
Speaker’ bureau, consulting agreement, research
grants from King and Wyeth Pharmaceuticals,
no stock , options or BOD Position

2
ALLHAT
AHT RATIONALE
• 50-60 million hypertensive patients in US
• Estimated Cost: $37 billion annually
• Drugs FDA approved on ability to lower BP
• CCB & ACE-I shown to reduce CVD-2001
• Are they all equal-clinical outcomes/AEs?
• Which drug should be used first?
– Relative Efficacy-unknown
– Relative Cost-known

3
Hypertension Treatment by Drug Class
% of Treated Patients on Medication
60
50
40
30
20
10
0
Diuretics
ß-Blocker Blocker
ACE Inhibitors
CCBs
Calcium Channel Blockers
Beta Blockers
Diuretics
ACE Inhibitors
ARBs
ARBs
1978 1981 1984 1987 1990
Year
1993 1996 1999 2002
IMS Health NDTI, 1978-2002 1978 2002

4
2002 Use of Antihypertensive Medications, Proportion
of Drug-Treated Patients by Drug Class
40%
37%
% Patients
30%
20%
10%
0%
ACE- ACE
Inhibitors
Source: NDTI -- IMS HEALTH
27%
Calcium
Channel
Blockers
20% 20% 19%
Diuretics Beta- Beta
Blockers
ARBs

5
ALLHAT
Antihypertensive
Trial Design
• Randomized, double-blind, multi-center
clinical trial
• Determine whether occurrence of fatal CHD or
nonfatal MI is lower for high-risk hypertensive
patients treated with newer agents (CCB,
ACEI, alpha-blocker) compared with a diuretic
• 42,418 high-risk hypertensive patients ≥ 55
years

6
ALLHAT
Secondary Objectives:
Pre-specified
–Age 65+
–Women
Subgroups
–African-Americans
–Diabetic patients
Post-hoc
–Baseline CHD

7
ALLHAT Pre-Specified Outcomes
All primary and secondary outcomes and their
components were pre-specified , i.e., they appeared in
the protocol, manual of operations and study forms.
Primary Outcome – Coronary Heart Disease (CHD) –
fatal CHD or non-fatal MI
Secondary Outcomes
1. All-cause death
2. Combined CHD [CCHD] (CHD, coronary
revascularizations, or hospitalized angina)
3. Stroke

8
ALLHAT
Pre-Specified Secondary
Outcomes (Continued)
4. Combined Cardiovascular Disease [CCVD]
(CHD, stroke, coronary revascularizations, heart failure
[treated, hospitalized, fatal], angina (treated, hospitalized),
peripheral arterial disease (revascularization procedure)
5. Left ventricular hypertrophy by ECG
6. Renal disease
a. Slope of reciprocal of creatinine
b. End-stage renal disease (dialysis or transplant)
7. HRQL; Major costs of medical care
8. Cancer
9. Gastrointestinal bleeding

9
ALLHAT
Inclusion Criteria for
Antihypertensive Trial
• Age/sex: men and women aged > 55 years
• BP eligibility:
–Untreated systolic and/or diastolic hypertension (≥
140/90 mm Hg but ≤ 180/110 mm Hg at two visits)
–Treated hypertension
• ≤ 160/100 mm Hg on 1-2 antihypertensive drugs at
Visit 1
• ≤ 180/110 mm Hg at Visit 2, when medication may
have been partially withdrawn
–No washout period was required in ALLHAT.

10
ALLHAT
ALLHAT Inclusion Criteria:
Risk Factors
At least one of the following:
• Myocardial infarction or stroke: at least 6
months old, or age-indeterminate
• History of revascularization procedure
• Major ST segment depression or T-wave
inversion
• Other documented ASCVD

11
ALLHAT
ALLHAT Inclusion
Criteria: Risk Factors
At least one of the following (cont.)
• Type 2 diabetes mellitus
• HDL cholesterol < 35 mg/dL on any 2 or
more determinations in past 5 years
• Left ventricular hypertrophy (past 2 years)
– ECG, or echo (septum + posterior wall
thickness ≥ 25 mm)
• Current cigarette smoking

12
ALLHAT
Major Exclusion Criteria
• MI, stroke, CHF, or angina within 6 months
• Ejection fraction < 35% within past 6
months
• Known renal insufficiency - creatinine ≥ 2
mg/dL
• Requiring diuretics, CCB, ACEI, or alpha
blockers for reasons other than
hypertension

13
ALLHAT
High-risk
hypertensive
patients
Eligible for lipidlowering
Consent / Randomize (10,355)
Pravastatin Usual care
Randomized Design
Consent /
Randomize
(42,418)
of ALLHAT
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Not eligible for
lipid-lowering
Follow for CHD and other outcomes until death or end of study (up to 8 yr).

14
ALLHAT
Step 1 Agent
Chlorthalidone
Amlodipine
Lisinopril
Doxazosin
* mg/day
Initial Dose*
12.5
2.5
10
1
Step 1
Treatment Protocol
Dose 1*
12.5
2.5
10
2
Dose 2*
12.5
5
20
4
Dose 3*
25
10
40
8

15
ALLHAT
Step 2 Agents:
Reserpine
Clonidine (oral)
Atenolol
Step 3 Agent:
Hydralazine
*All doses in mg
Step Up
Treatment Protocol
Dose 1*
0.05 qd
or 0.1 qod
0.1 bid
25 qd
25 bid
Dose 2*
0.1 qd
0.2 bid
50 qd
50 bid
Dose 3*
0.2 qd
0.3 bid
100 qd
100 bid

16
ALLHAT
Decision to Drop
an ALLHAT Arm
• January 24, 2000 – NHLBI Director accepts
the recommendation of an independent
review group to terminate doxazosin arm
– Futility of finding a significant difference
for primary outcome
– Statistically significant 25 percent higher
rate of major secondary endpoint,
combined CVD outcomes

17
Cumulative Event Rate
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 1 2 3 4
C: 15,268
D: 9,067
Cardiovascular Disease
Rel Risk
1.25
doxazosin
12,990
7,382
95% CI
1.17-1.33
z = 6.77, p < 0.0001
chlorthalidone
9,443
5,285
Years of Follow-up
ALLHAT
4,827
2,654
2,010
1,083
JAMA. 2000;283:1967-1975

18
Cumulative Event Rate
0.10
0.08
0.06
0.04
0.02
0.00
C: 15,268
D: 9,067
Heart Failure
Rel Risk
2.04
doxazosin
95% CI
1.79-2.32
z = 10.95, p < 0.0001
Years of Follow-up
ALLHAT
chlorthalidone
9,541 5,531 2,427
13,644
5,457 3,089 1,351
0 1
7,845
2 3 4
JAMA. 2000;283:1967-1975

19
ALLHAT
100.0
80.0
60.0
%
40.0
20.0
0.0
On Step 1 or Equivalent Treatment by
Antihypertensive Treatment Group
1 Year 2 Years 3 Years 4 Years 5 Years
Chlor 87.1 84.7 82.7 80.8 80.5
Aml 87.6 85.2 83.2 80.5 80.4
Lis 82.4 78.4 77.1 74.8 72.6

20
ALLHAT
Percent
100
80
60
40
20
0
Use of Blinded (Step 1) Drug and Number of
Antihypertensive Drugs Prescribed
On 1 Drug
On 2 Drugs
On 3 Drugs
On Step 1 Drug
0 12 24 36 48 60
Months of Follow-Up
@ 5 years: 62% were on >2 2 drugs
30% were on 1 drug with BP

21
ALLHAT
mm Hg BP
150
145
140
135
130
Chlorthalidone Amlodipine Lisinopril
0 1 2 3 4 5 6
Years
Compared to chlorthalidone:
SBP significantly higher in the
amlodipine group (~1 mm Hg) and
the lisinopril group (~2 mm Hg).
BP Results by Treatment Group
mm Hg BP
90
85
80
75
70
0 1 2 3 4 5 6
Years
Compared to chlorthalidone:
DBP significantly lower in the
amlodipine group (~1 mm Hg).

22
Percent
ALLHAT
100
80
60
40
20
0
31
Blood Pressure Control
86%
1.6 = mean number of drugs
88%
90%
91%
92%
68%
58 60
64 67 67
62 65 66
55
58
27
DBP

23
Percent
ALLHAT
80
60
40
20
0
59
Percent of Uncontrolled
Not Stepped Up
68
69
72 72
1 2 3 4 5
Years
J Clinical Hypertens 2002; 4:393-404
4:393 404

24
ALLHAT
Cumulative CHD Event Rate
.2
.16
.12
.08
.04
0
L/C
Cumulative Event Rates for the Primary
Outcome (Fatal CHD or Nonfatal MI) by
ALLHAT Treatment Group
A/C
RR (95% CI)
0.98 (0.90-1.07)
0.99 (0.91-1.08)
Chlorthalidone
Amlodipine
Lisinopril
p value
0 1 2 3 4 5 6 7
Years to CHD Event
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
0.65
0.81

25
ALLHAT
Cumulative Stroke Rate
.1
.08
.06
.04
.02
0
A/C
L/C
Cumulative Event Rates for Stroke by
ALLHAT Treatment Group
RR (95% CI)
0.93 (0.81-1.06)
1.15 (1.02-1.30)
Chlorthalidone
Amlodipine
Lisinopril
p value
0.28
0.02
0 1 2 3 4 5 6 7
Years to Stroke
Number at risk:
Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567
Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506
Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

26
ALLHAT
Total 0.93 (0.82, 1.06)
Age < 65 0.93 (0.73, 1.19)
Age >= 65 0.93 (0.81, 1.08)
Men 1.00 (0.85, 1.18)
Women 0.84 (0.69, 1.03)
Black 0.93 (0.76, 1.14)
Non-Black 0.93 (0.79, 1.10)
Diabetic 0.90 (0.75, 1.08)
Non-Diabetic 0.96 (0.81, 1.14)
0.50 1 2
Amlodipine Better Chlorthalidone Better
Stroke – Subgroup Comparisons –
RR (95% CI)
Total 1.15 (1.02, 1.30)
Age < 65 1.21 (0.97, 1.52)
Age >= 65 1.13 (0.98, 1.30)
Men 1.10 (0.94, 1.29)
Women 1.22 (1.01, 1.46)
Black 1.40 (1.17, 1.68)
Non-Black 1.00 (0.85, 1.17)
Diabetic 1.07 (0.90, 1.28)
Non-Diabetic 1.23 (1.05, 1.44)
0.50 1 2
Lisinopril Better Chlorthalidone Better
P = .01 for interaction

27
ALLHAT
Cumulative Mortality Rate
.3
.25
.2
.15
.1
.05
0
Cumulative Event Rates for All-Cause
Mortality by ALLHAT Treatment Group
A/C
L/C
HR (95% CI)
0.96 (0.89-1.02)
1.00 (0.94-1.08)
Chlorthalidone
Amlodipine
Lisinopril
p value
0.20
0.90
0 1 2 3 4 5 6 7
Years to Death
Number at risk:
Chlor 15,255 14,933 14,564 14,077 12,480 7.185 3,523 4288
Amlo 9,048 8,847 8,654 8,391 7,442 4,312 2,101 217
Lisin 9,054 8,853 8,612 8,318 7,382 4,304 2,121 144

28
ALLHAT
Cumulative Combined CVD Event Rate
.5
.4
.3
.2
.1
0
A/C
L/C
Cumulative Event Rates for Combined
CVD by ALLHAT Treatment Group
RR (95% CI)
1.04 (0.99-1.09)
1.10 (1.05-1.16)
Chlorthalidone
Amlodipine
Lisinopril
p value
0.12

29
ALLHAT
Total 1.04 (0.99, 1.09)
Age < 65 1.03 (0.94, 1.12)
Age >= 65 1.05 (0.99, 1.12)
Men 1.04 (0.98, 1.11)
Women 1.04 (0.96, 1.13)
Black 1.06 (0.96, 1.16)
Non-Black 1.04 (0.97, 1.10)
Diabetic 1.06 (0.98, 1.15)
Non-Diabetic 1.02 (0.96, 1.09)
0.50 1 2
Combined CVD – Subgroup
Comparisons – RR (95% CI)
Amlodipine Better Chlorthalidone Better
Total 1.10 (1.05, 1.16)
Age < 65 1.05 (0.97, 1.15)
Age >= 65 1.13 (1.06, 1.20)
Men 1.08 (1.02, 1.15)
Women 1.12 (1.03, 1.21)
Black 1.19 (1.09, 1.30)
Non-Black 1.06 (1.00, 1.13)
Diabetic 1.08 (1.00, 1.17)
Non-Diabetic 1.12 (1.05, 1.19)
0.50 1 2
Lisinopril Better Chlorthalidone Better
P = .04 for interaction

30
ALLHAT
Cumulative CHF Rate
.15
.12
.09
.06
.03
0
Cumulative Event Rates for Heart Failure
by ALLHAT Treatment Group
A/C
L/C
HR (95% CI)
1.38 (1.25-1.52)
1.19 (1.07-1.31)
Chlorthalidone
Amlodipine
Lisinopril
p value

31
ALLHAT
Total 1.38 (1.25, 1.52)
Age < 65 1.51 (1.25, 1.82)
Age >= 65 1.33 (1.18, 1.49)
Men 1.41 (1.24, 1.61)
Women 1.33 (1.14, 1.55)
Black 1.47 (1.24, 1.74)
Non-Black 1.33 (1.18, 1.51)
Diabetic 1.42 (1.23, 1.64)
Non-Diabetic 1.33 (1.16, 1.52)
0.50 1 2
Amlodipine Better Chlorthalidone Better
Heart Failure – Subgroup
Comparisons – RR (95% CI)
Total 1.20 (1.09, 1.34)
Age < 65 1.23 (1.01, 1.50)
Age >= 65 1.20 (1.06, 1.35)
Men 1.19 (1.03, 1.36)
Women 1.23 (1.05, 1.43)
Black 1.32 (1.11, 1.58)
Non-Black 1.15 (1.01, 1.30)
Diabetic 1.22 (1.05, 1.42)
Non-Diabetic 1.20 (1.04, 1.38)
0.50 1 2
Lisinopril Better Chlorthalidone Better

32
ALLHAT
Overall Conclusions
Because of the superiority of thiazide-type
diuretics in preventing one or more major
forms of CVD and their lower cost, they
should be the drugs of choice for first-step
antihypertensive drug therapy.

33
ALLHAT
AHT: TOTAL CHD AND ALL CAUSE
MORTALITY OUTCOMES
NO DIFFERENCES BETWEEN
CHLORTHALIDONE AND AMLODIPINE
OR
CHLORTHALIDONE AND LISINOPRIL

34
ALLHAT
BLOOD PRESSURE CONTROL KEY
TO REDUCE OUTCOMES
ALLHAT PROVIDES EVIDENCE:
HOW ONE CONTROLS BP MATTERS!!
THIS IS BASED ON ANALYSES OF
SECONDARY OUTCOMES.

35
ALLHAT
Antihypertensive Trial:
Implications
• Switch those on other anti-hypertensives –even
those well-controlled.
-Superior outcomes with diuretic
-$1 billion saved for 2 million switched
• We HAVE effective anti-hypertensive agents.
Control elevated blood pressure. (

36
SECOND AUSTRALIAN NATIONAL
BLOOD PRESSURE STUDY (ANBP-2)
• Enalapril/ACEI vs. HCTZ, n = 6,083
• Randomized, open-label (blinded endpoint review)
• All CV events or death from any cause
– HR = 0.89 (0.79-1.00), p=0.05 (adjusted)
• First events
– CVD: HR = 0.88 (0.77-1.01), p = 0.07
– CHD: HR = 0.86 (0.70-1.06), p = 0.16
– Stroke: HR = 1.02 (0.78-1.33), p = 0.91
– HF: HR = 0.85 (0.62-1.18), p = 0.33
NEJM 2003;348:583-92

38
ALLHAT vs. ANBP-2
• Randomized double-blind vs. PROBE design
• ACEI vs. thiazide-type diuretic, n = 24,309 vs. 6,083
• Number of patients with events
– CVD: n = 6,455 vs. 823
– CHD: n = 3,956 vs. 368
– Stroke: n = 1,132 vs. 219
– Heart failure: n = 1,482 vs. 147
• Treatment differences consistent across gender
subgroup vs. differences noted only in men
• SBP slightly lower with diuretic in both trials

39
DOES ALLHAT TRUMP
HOPE?
• Different populations-ALLHAT, HBP,
HOPE, not.
• ACE-I used to control BP in ALLHAT
• Different ACE-I used: lack proof of Class
Effect
ALLHAT does not trump HOPE

Primary Adjudicated Events
- Ramipril vs Placebo 1/2
Ramipril
(%)
No. Rand. 4645 4652
1°Outcome
Placebo
(%)
RR 95% CI p
MI,Stroke,CVDth 14.1 17.7 0.78 0.70-0.86 0.000002
CV Death* 6.1 8.1 0.75 0.64-0.87 0.0002
MI* 9.9 12.2 0.80 0.71-0.91 0.0005
Stroke* 3.4 4.9 0.69 0.56-0.84 0.0003
Non-CV Death 4.3 4.1 1.03 0.84-1.25 0.78
Mortality 10.4 12.2 0.84 0.75-0.95 0.0058
*not mutually exclusive

Kaplan-Meier Rates
0.2
0.15
0.1
0.05
0
Primary Outcome -
Ramipril vs Placebo
0 500 1000 1500
RR=0.78 (0.70-
0.86)
Ramipril Placebo
Days of Follow-up
P=0.000002

DOES OBSERVED BP
REDUCTION ACCOUNT FOR
HOPE EVENT RESULTS?

Mean Change in Blood Pressure -
Ramipril vs Placebo
Arm Systolic BP
Ramipril
Placebo
Arm Diastolic BP
Ramipril
Placebo
Baseline Value 1 Month ∆ 2 Year ∆ End ∆
(mmHg)
138.50
138.85
78.91
78.92
-5.51
-1.69
-2.73
-0.56
-3.32
0.00
-2.86
-1.01
-2.19
0.38
-3.14
-2.06

Quartiles
≤124
125-139
140-150
151+
Overall
Risk of CV Death / MI / Stroke
by SBP
Usual
BP
125
134
142
153
P for trend=0.06
RR with 95% CI
Abs.
Risk
Reductio
n
2.7%
2.5%
2.0%
7.9%
3.6%
Ramipril better Ramipril worse
N
2281
2465
2438
2110

Risk Reductions for Stroke and MI:
Predicted versus Observed
Source
Previous Studies
HOPE Placebo
HOPE Ramipril
Previous Studies
HOPE Placebo
SBP – Red
mm Hg
3.3
3.3
3.3
10-15
10
Stroke
(RRR%)
13
7
32
40
23
MI
(RRR%)
5
6
20
15
17

SUBGROUP RESULTS BY
OTHER DRUG THERAPY
(PRIMARY +REVASC+ALL CHF)
Beta + 32.3%
Blockers - 28.4%
CCB + 34.3%
- 26.1%
Diuretics + 36.3%
- 28.7%
Any of the
Above
Ramipril Placebo RR(95%Cl)
+ 32.7%
- 22.2%
37.9%
34.3%
39.1%
32.6%
43.2%
34.4%
37.4%
30.7%
0.82 (0.74,0.92)
0.80 (0.72,0.87)
0.85(0.77,0.94)
0.77(0.69,0.85)
0.81(0.69,0.96)
0.80(0.74,0.87)
0.84(0.78,0.91)
0.69(0.59,0.81)

47
WEB SITE
www.nhlbi
www. nhlbi.nih nih.gov gov/

48
Blood Pressure Classification
BP Classification
Normal
Prehypertension
Stage 1
Hypertension
Stage 2
Hypertension
SBP mmHg
160 160
and
or
or
or
DBP mmHg
100 100

49
Office BP Measurement
� Use auscultatory method with a properly calibrated and
validated instrument.
� Patient should be seated quietly for 5 minutes in a
chair
(not on an exam table), feet on the floor, and arm
supported at heart level.
� Appropriate-sized cuff should be used to ensure
accuracy.
� At least two measurements should be made.
� Clinicians should provide to patients, verbally and in
writing, specific BP numbers and BP goals.

50
New Features and Key
Messages
�� For persons over age 50, SBP is a more important than
DBP as CVD risk factor.
�� Starting at 115/75 mmHg, CVD risk doubles with each
increment of 20/10 mmHg throughout the BP range.
�� Persons who are normotensive at age 55 have a 90%
lifetime risk for developing HTN.
�� Those with SBP 120–139 120 139 mmHg or DBP 80–89 80 89 mmHg
should be considered prehypertensive who require
health-promoting health promoting lifestyle modifications to prevent
CVD.

51
New Features and Key
Messages (Continued)
� Thiazide-type diuretics should be initial drug therapy
for most, either alone or combined with other drug
classes.
� Certain high-risk conditions are compelling
indications for other drug classes.
� Most patients will require two or more
antihypertensive drugs to achieve goal BP.
� If BP is >20/10 mmHg above goal, initiate therapy
with two agents, one usually should be a thiazidetype
diuretic.

52
New Features and Key
Messages (Continued)
� The most effective therapy prescribed by the careful
clinician will control HTN only if patients are motivated.
� Motivation improves when patients have positive
experiences with, and trust in, the clinician.
� Empathy builds trust and is a potent motivator.
� The responsible physician’s judgment remains
paramount.

53
Lifestyle Modification
Modification
Weight reduction
Adopt DASH eating
plan
Dietary sodium
reduction
Physical activity
Moderation of
alcohol consumption
Approximate SBP reduction
(range)
5–20 20 mmHg/10 kg weight loss
8–14 14 mmHg
2–8 8 mmHg
4–9 9 mmHg
2–4 4 mmHg

54
Algorithm for Treatment of
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (100 mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
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
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.

55
Diuretic Use Pre- Pre and Post-ALLHAT
Post ALLHAT
NRxs
1,800,000
1,600,000
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
IMS
New Prescriptions for Diuretic Sub-classes
(Unallocated)
Jan-
02
Feb-
02
Mar-
02
Apr-
02
May-
02
Jun-
02
Jul-
02
Aug-
02
Sep-
02
Oct-
02
No v-
02
Dec-
02
Thiazide Potassium-sparing Loop
Jan-
03
Feb-
03
Mar-
03
NRxs
1,200,000
1,000,000
800,000
600,000
400,000
200,000
-
Jan-
02
New Prescriptions for Chlorthalidone &
Hydrochlorothiazide
(Unallocated)
Feb-
02
Mar-
02
Apr-
02
May-
02
Jun-
02
Jul-
02
Aug-
02
Sep-
02
Oct-
02
Nov-
02
Dec-
02
Jan-
03
CHLORTHALIDONE HYDROCHLOROTHIAZIDE
Feb-
03
Mar-
03