Transcript ALLHAT - Emory University Department of Medicine

Are All
Antihypertensives
The Same?
Birju B. Patel, M.D.
Geriatric Medicine Trainee
Emory University School of Medicine, Division of Geriatrics
June 5th, 2003
Journal Club
Why did I choose this topic?

Deep interest in the topic of HTN

New guidelines (JNC VII) – media coverage

Seemingly contradictory trials (ALLHAT vs.
ANBP2)

Lack of BP control in most patients!

So many choices in medications …
What are we going to talk about?

Background and impact of HTN

JNC VI and VII goals, recommendations

ALLHAT trial synopsis

ANBP2 trial

Comparison of these two trials

Take home lessons

Discussion & questions
Background
First direct measurement of blood
pressure

There was no direct means to
measure the arterial pressure until
1733 when Stephen Hales sacrificed
his horse in his back yard by
measuring the height of a column of
blood extending from the carotid
artery into a glass tube from the
time of cannulation until the horses'
death.
1896 - Riva-Rocci’s first inflatable
rubber cuff
Auscultatory method described by
Korotkoff
Korotkoff, 1905
“Antihypertensive agents produce no
obvious benefit in patients over 65”
Fry J, Lancet 1974
“Hypertensive drugs should probably not
be given (in the elderly) unless the blood
pressure is more than 200/110 mm Hg.”
Editorial, Br Med J, 1978
Cardiovascular Disease
is the #1 Cause of Death
in the US
2001 Heart and Stroke Statistical Update. American Heart Association.
Prevalence of Cardiovascular Disease
Estimated Number of Persons With
Cardiovascular Disease in the US
Prevalence (millions)
10
20
30
60
12,200,000
CHF
4,600,000
Stroke
4,400,000
Other
50
50,000,000 (24%)
High BP
CAD
40
2,800,000
BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure
American Heart Association® . 2000 Heart and Stroke Statistical Update. 1999.
A Public Health Crisis
60.8 MILLION AMERICANS
HAVE CARDIOVASCULAR DISEASE

High BP: 50 million
–

Coronary heart disease: 12.4 million
–
–


#1 Cardiovascular Disease
Myocardial infarction: 7.3 million
Angina pectoris: 6.4 million
Stroke: 4.5 million
CHF: 4.7 million
2001 Heart and Stroke Statistical Update. American Heart Association.
Hypertension in the elderly
 More than two-thirds of people over 65 have
HTN.
 This population has the lowest rates of BP
control.
 Isolated systolic HTN is common.
 Lower initial drug doses may be used to avoid
symptoms; standard doses and multiple drugs
will be needed to reach BP targets.
Adapted from JNC VII. JAMA. 2003;298:2560-2572
Millimeters Matter...
“A 2-mm Hg reduction in DBP
would result in…
a 6% reduction in the risk of CHD
and a 15% reduction
in the risk of stroke and TIAs”
Cook, et al. Arch Int Med. 1995;155:701-709.
Development of
Antihypertensive Therapies
Effectiveness
Tolerability
1940’s
1950
1960’s
1957
-blockers
Direct
vasodilators
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
1970’s
1980’s
1990’s
2001
ARBs
ACE
inhibitors
Others
Thiazides
diuretics
Central 2
agonists
Calcium
antagonistsnon DHPs
-blockers
Calcium
antagonistsDHPs
Treated hypertensive subjects with BP <140/90
mmHg
28%
22%
USA
Canada
6%
UK
9%
3%
India
China
<140/90 mmHg
140/90 mmHg
24%
France
27%
Italy
25%
Belgium
2%
10%
Zaire
Egypt
Approximately 50 Million Americans
Have Hypertension
13.7 million
Controlled
27.4%
36 million
Uncontrolled
72.6%
American Heart Association, February 1999.
JNC VI
BP Classification
BP (mm Hg)
Category
Systolic
Diastolic
Optimal
120
and
80
Normal
130
and
85
High-normal
130–139
or
85–89
Hypertension
stage 1
stage 2
stage 3
140–159
160–179
180
or
or
or
90–99
100–109
110
Adapted from JNC VI. Arch Intern Med. 1997;157:2413-2446.
JNC VII
BP Classification
SBP mmHg
Normal
<120
DBP mmHg
and
<80
Prehypertension 120–139
or
80–89
Stage 1 HTN
140–159
or
90–99
Stage 2 HTN
>160
or
>100
*Approximately 45 million americans fall into prehypertensive category
Adapted from JNC VII. JAMA. 2003;298:2560-2572
Hypertension
“The greatest danger to a man with
high blood pressure lies in its
discovery, because then some fool
is certain to try and reduce it.”
Brit Med J 1931;2:43-7.
Lifestyle Modification
Modification
Approximate SBP reduction
(range)
Weight reduction
5–20 mmHg/10 kg weight loss
DASH eating plan
8–14 mmHg
sodium reduction
2–8 mmHg
Physical activity
4–9 mmHg
Moderation of
alcohol
2–4 mmHg
Adapted from JNC VII. JAMA. 2003;298:2560-2572.
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 who are prehypertensive require health-promoting lifestyle
modifications to prevent CVD.
Adapted from JNC VII. JAMA. 2003;298:2560-2572
New Features and Key Messages
 Thiazide 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 thiazide-type diuretic.
Adapted from JNC VII. JAMA. 2003;298:2560-2572
ALLHAT
U.S. Department of
Health and Human
Services
National Institutes
of Health
Major Outcomes in High Risk Hypertensive
Patients Randomized to AngiotensinConverting Enzyme Inhibitor or Calcium
Channel Blocker vs Diuretic
The Antihypertensive and LipidLowering Treatment to Prevent Heart
Attack Trial (ALLHAT)
The ALLHAT Collaborative Research Group
Sponsored by the National Heart, Lung, and Blood
Institute (NHLBI)
National Heart, Lung,
and Blood Institute
JAMA. 2002;288:2981-2997
ALLHAT
42,418 patients with hypertension



Diuretic
Chlorthalidone
12-25 mg/day
(n=15,255)
SBP >140mmHg and/or DBP >90 mmHg OR
Took medication for hypertension and had at least one additional risk
factor for CHD
Age 55-79, mean age: 67 yrs
Calcium Channel
Blocker
Amlodipine
2.5-10 mg/day
(n=9,048)



ACE Inhibitor
Lisinopril
10-40 mg/day
(n=9,054)
Alpha Blocker
Doxazosin*
2-8 mg/day
(n=9,061)
Endpoints:
Primary – Fatal coronary heart disease and nonfatal MI
Secondary – All-cause mortality, stroke, and major
cardiovascular disease events (CHF, coronary
revascularization, angina, and peripheral artery disease)
Mean follow-up 4.9 years
* Discontinued prior to study completion
JAMA 2002;288:2981-2997
ALLHAT: Primary Endpoint*
Chlorthalidone vs Amlodipine
Primary Endpoint
RR = 0.98
15%
p = 0.65
11.5%
15%
Chlorthalidone vs Lisinopril
Primary Endpoint
RR = 0.99
p = 0.81
11.5%
11.3%
10%
10%
5%
5%
0%
0%
Chlorthalidone Amlodipine
11.4%
Chlorthalidone Lisinopril
* Primary Endpoint = Fatal CHD or nonfatal MI JAMA 2002;288:2981-2997
Secondary Endpoints
20%
Chlorthalidone vs Amlodipine
All Cause Mortality
Heart Failure
RR = 0.96
RR = 1.38
15%
p = 0.20
p < 0.001
17.3%
16.8%
10.2%
15%
10%
7.7%
10%
5%
5%
0%
0%
Chlorthalidone Amlodipine
Chlorthalidone Amlodipine
JAMA 2002;288:2981-2997
Secondary Endpoints
Chlorthalidone vs Lisinopril
20%
All Cause Mortality
RR = 1.00
p = 0.90
17.3%
15%
Heart Failure
RR = 1.19
p < 0.001
10%
Stroke
RR = 1.15
p = 0.02
17.2%
8%
15%
10%
8.7%
7.7%
6.3%
6%
5.6%
10%
4%
5%
5%
2%
0%
ChlorthalidoneLisinopril
0%
ChlorthalidoneLisinopril
0%
ChlorthalidoneLisinopril
JAMA 2002;288:2981-2997
ALLHAT Conclusions

Better control of systolic BP was achieved with
chlorthalidone than with amlodipine or lisinopril

There were no differences in risk for CHD death/nonfatal
MI between chlorthalidone and amlodipine or lisinopril

In secondary endpoints, chlorthalidone was associated
with lower risk for
–
stroke, combined CVD, and HF compared with
lisinopril
–
HF compared with amlodipine
MI=myocardial infarction
CHD=coronary heart disease
HF=heart failure
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
ALLHAT Implications

Unless contraindicated, or unless specific indications
are present that would favor use of another drug class,
diuretics should be the initial drug of choice in
antihypertensive regimens

Only 30 percent of patients achieve both systolic BP
<140 mmHg and diastolic BP <90 mmHg on
monotherapy

Many high-risk hypertensive patients will require 2 or
more drugs for BP control
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
ALLHAT: Limitations
Add-on therapy
 Especially atenolol not ideal and not synergistic for ACEI
group.
Large crossover rate by 4 year follow-up
ACEI known to be less effective in blacks and also
less well tolerated.
ANBP2 trial at a glance…

Prospective, randomized, open-label study
with blinded assessment of end points.

6083 subjects with hypertension

Aged 65 to 84 years

1594 family practices throughout Australia.

The ACE inhibitor enalapril or the diuretic
hydrochlorothiazide were recommended as
initial therapy; however, the choice of the
specific agent and dose was made by the
family practitioner.
Inclusion criteria

Average systolic at least 160 mm Hg or an
average diastolic of at least 90 mm Hg.

Absence of recent CV event in 6 months

Informed consent
Exclusion criteria

Life threatening illness

Contraindication to ACEI or diuretic

Creatinine > 2.5 mg/dl

Malignant hypertension

Dementia
ANBP2 trial



To achieve the blood-pressure goals
(<160/90), the addition of beta blockers,
calcium channel blockers, and alpha blockers
was recommended in both groups.
Subjects were followed for a median of 4.1
years.
At baseline the treatment groups were similar
in terms of age, sex, blood pressure,
previous treatment of BP, BMI, tobacco and
alcohol use, level of physical activity, hx of
CAD, CVD, DM, and Hypercholestrolemia.
BP decreased to a similar extent in both
groups (a decrease of 26/12 mm Hg).
Table 2

Hazard ratio of all cardiovascular events or
death from any cause in ACEI group vs.
diuretic group was 0.89 (95 percent
confidence interval, 0.79 to 1.00; P=0.05)

11% reduction in total burden of CV events
or death of any cause.

32 subjects of either sex or 23 men need to
be treated with ACEI to prevent one
additional first CV event or death in first five
years after treatment.
Limitations of ANBP2

Open-labeled design and lack of step up
protocol allows bias in treatment approach

Limited statistical power, smaller study,
lower risk population

Only 58% of ACEI group and 62% of diuretic
group were receiving assigned treatment at
end of study.
ALLHAT vs. ANBP2






Lower initial bp in ALLHAT trial vs. ANBP2
More caucasian (lack of black subjects) and
low CV risk subjects in ANBP2 vs. ALLHAT
(35% black subjects in ALLHAT)
More diabetics 36% in ALLHAT vs. 7% in
ANBP2.
Open label vs. double-blinded design
ALLHAT trial much larger
ALLHAT with well defined protocol of
starting dose, titration, and add-ons.
Take home points

ACEIs have good outcome evidence in nonblack hypertensive patients ALLHAT

Low-dose thiazides have outcome advantages
over ACEIs in black patients. ALLHAT

Low-dose thiazides have good outcome
evidence in elderly patients with CV risk factors
(including diabetes) ALLHAT

Low-dose thiazides good evidence in females
ALLHAT, ANBP2
Take home points

ACEIs have good outcome evidence in
caucasian hypertensive male patients; lowdose thiazides also have good evidence ALLHAT
& given limitations of ANBP2 trial design.

ACEIs and low-dose thiazides work
synergistically & are a logical combination
option in non-black patients

CAUTION: very different study designs and
population groups limit comparison
Collaboration can get us a long way….