Transcript Coaated stents: a new era

ALLHAT
ALLHAT: Optimal first-step therapy
for hypertension
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
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ALLHAT
Randomized design
of ALLHAT
High-risk
hypertensive
patients
Consent /
Randomize
(42 418)
Eligible for lipidlowering
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Not eligible for
lipid-lowering
Consent / Randomize (10
355)
Pravastatin
Usual care
Follow for CHD and other outcomes until death or end of
study (updown
to 8–yrs).
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ALLHAT
A horse race
Each class of antihypertensive is
represented by a drug, and the
losers drop out as events are
accrued
Primary end point: fatal CHD or
nonfatal MI
All major clinical end points were
measured in minimal detail
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Califf
ALLHAT
Secondary drug protocol
Step 2 agents:
Reserpine
Dose 1*
Dose 2*
Dose 3*
0.05 qd
or 0.1 qod
0.1 qd
0.2 qd
0.1 bid
0.2 bid
0.3 bid
25 qd
50 qd
100 qd
25 bid
50 bid
100 bid
Clonidine (oral)
Atenolol
Step 3 agent:
Hydralazine
*All doses in mg
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ALLHAT
ALLHAT: Trial design
• 42 418 patients age >55 with hypertension
and 1 additional risk factor
• 623 sites:
United States
Canada
Puerto Rico
US Virgin Islands
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ALLHAT
Doxazosin CVD end point
Cumulative event rate
0.30
0.25
doxazosin
0.20
chlorthalidone
0.15
Rel risk
1.25
0.10
0.05
12,990
7,382
9,443
5,285
95% CI
1.17-1.33
z = 6.77,
4,827 p < 0.0001
2,010
2,654
1,083
0.00
0
C: 15,268
D: 9,067
1
2
Years of Follow-up
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3
4
JAMA. 2000;283:1967-1975
ALLHAT
ALLHAT: Primary end point
Chlorthalidone
Lisinopril
Amlodipine
12.0
Events (%)
10.0
8.0
6.0
4.0
2.0
0.0
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JAMA 2002; 288:2981-2997
ALLHAT
Lisinopril secondary end points
Chlorthalidone
Lisinopril
6-year event rate
(per 100 persons)
9
8
7
6
5
4
3
2
1
0
Heart failure
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Stroke
JAMA 2002; 288:2981-2997
ALLHAT
Amlodipine secondary end points
Chlorthalidone
Amlodipine
6-year event rate
(per 100 persons)
12
10
8
6
4
2
0
Heart failure
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Stroke
JAMA 2002; 288:2981-2997
ALLHAT
ALLHAT: Fasting glucose levels
Chlorthalidone
Lisinopril
Amlodipine
Fasting glucose >
126 mg/dL (%)
35
30
25
20
15
10
5
0
Baseline
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2 years
4 years
JAMA 2002; 288:2981-2997
ALLHAT
Stroke risk: Lisinopril vs
chlorthalidone
Subgroup
Relative risk
95% CI
Nonblack
1.00
0.85-1.17
Black
1.40
1.17-1.68
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JAMA 2002; 288:2981-2997
ALLHAT
ALLHAT: Glomerular filtration rate
Filtration rate
mL/min per 1.73
sq m
Chlorthalidone
78
76
74
72
70
68
66
64
62
60
Baseline
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Lisinopril
2 years
Amlodipine
4 years
JAMA 2002; 288:2981-2997
ALLHAT
ALLHAT-LLT: Primary results
Pravastatin
Usual care
6-year event rate/
100 patients
16
14
12
10
8
6
4
2
0
Mortality
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CHD and nonfatal MI
JAMA 2002; 288:2998-3007
ALLHAT
ALLHAT-LLT: Disappointing
Second largest statin trial after HPS
"[It's] disappointing that it didn't
provide true consistency and
only with this bouillabaisse
pooling stuff do you get the
same relative effect."
Topol
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ALLHAT
ALLHAT: Points of contention
Why did lisinopril increase heart
failure and stroke?
This is directly opposite of the results
from HOPE
PEACE and EUROPA are looking at ACE
inhibitors as a key preventive tactic
"This backfired terribly in ALLHAT."
Topol
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ALLHAT
Active control trial
The other drugs were only less
effective than the diuretic, not
increasing risks for the patients
The "soft underbelly" of HOPE was
whether the patients were being
adequately treated with regard to
their other risk factors
If EUROPA and PEACE are negative,
either HOPE was wrong or ramipril
is "a magic potion"
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Califf
ALLHAT
Using less ramipril
I've gone from requiring ramipril use
to making it optional
"I think we have to say this is a
piece of data that moves back
toward less radical enthusiasm
about the ACE-inhibitor class."
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Califf
ALLHAT
ALLHAT: Blood pressure
Systolic BP (mm Hg)
Chlorthalidone
Lisinopril
Amlodipine
150
145
140
135
130
125
0
1
2
3
4
5
Years
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JAMA 2002; 288:2981-2997
ALLHAT
Genetics of hypertension
Studies suggest the genetic defect of
essential hypertension alpha —
adducin Gly460Trp would be
particularly responsive to thiazide
diuretic
Topol
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ALLHAT
Stroke risk: Lisinopril vs
chlorthalidone
Subgroup
Relative risk
95% CI
Nonblack
1.00
0.85-1.17
Black
1.40
1.17-1.68
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JAMA 2002; 288:2981-2997
ALLHAT
ALLHAT: Blood pressure
Systolic BP (mm Hg)
Chlorthalidone
Lisinopril
Amlodipine
150
145
140
135
130
125
0
1
2
3
4
5
Years
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JAMA 2002; 288:2981-2997
ALLHAT
Amlodipine secondary end points
Chlorthalidone
Amlodipine
6-year event rate
(per 100 persons)
12
10
8
6
4
2
0
Heart failure
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Stroke
JAMA 2002; 288:2981-2997
ALLHAT
Edema or heart failure?
There was no objective measure of
function to diagnose heart failure
A substudy was commissioned to have
records independently reviewed
All the results are not in, but so far
the substudy suggests that there is
more than just edema going on
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Califf
ALLHAT
Surprising increase in heart failure
The increase in heart failure for both
classes of drugs (ACE inhibitor and
CCB) was a very surprising finding
• Lisinopril 19% increased risk
• Amlodipine 38% increased risk
"You would have thought both drugs
would not have done this."
Topol
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ALLHAT
Bad choice of second drug
Critics say the second drug after ACE
inhibitor would be a diuretic,
forbidden by the trial
Most doctors in the US probably don't
use a diuretic as the second drug
"I think no matter how you slice the
loaf here the answer is that the
underused diuretics, which are a
lot cheaper, are at least as good
and almost certainly better."
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Califf
ALLHAT
A class effect?
Most doctors use hydrochlorothiazide
as a diuretic
This could be a chlorthalidone-specific
result, you can't be sure
"We have examples where drugs in
the same class don't get the
same results."
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Califf
ALLHAT
Striking secondary outcomes
The media loved that a cheaper drug
came out better
I wasn't enthusiastic about the trial
when I was on the NIH advisory
committee reviewing the trial
"The secondary outcomes made for
all the spice here. If you were to
just go by the primary outcome,
though, you wouldn't be able to
differentiate the treatments."
Topol
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ALLHAT
Public health
Why not use a cheaper drug that is
just as good? It's a dominant
treatment
A company trying to get labelling with
this primary outcome might have
trouble getting approval from the
FDA
"We have examples where drugs in
the same class don't get the
same results."
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Califf
ALLHAT
An easy choice
There is a value judgment being made
among the secondary outcomes
"I think the majority of people, if
you said, 'Look, I can give you
this thing for 2 cents a day, or I
can give you this thing for a buck
and a half a day, and here are the
expected outcomes, which would
you buy?' I don't think that's a
hard choice."
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Califf
ALLHAT
Inadequate treatment
"None of these drugs are very good,
they all have some untoward
effects, unfortunately. You're
picking your poison in some
respects."
This study reinforces that there is
inadequate treatment of blood
pressure.
"A lot of people are walking around
with very high blood pressure
still, despite therapy."
Topol
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ALLHAT
Lowering blood pressure
"I think that people that are most
critical of doctors trying to lower
blood pressure are people that
have never actually worked in a
clinic trying to get blood pressure
down."
It takes the doctor and patient
working together to get blood
pressure down
We usually need more than 2 drugs
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Califf
ALLHAT
Genomics approach to
hypertension
Genomics will allow us to move past
the trial and error approach
"$37 billion a year it costs to treat
hypertension and we're not even
doing a very good job of doing
it. We've got to have a better
strategy and almost any strategy
would be better than what we
have today."
Topol
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ALLHAT
Interpersonal approach
People will round numbers down for
patients who are frustrated at not
getting hypertension under control
to avoid adding more drugs drugs
Lowering blood pressure is very
complicated and interpersonal
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Califf
ALLHAT
Two thumbs up
Topol: "Don't you think this is as good
as it gets for hypertension and
clinical trials?"
• Two thumbs up
Califf: "I think it's as good as it gets."
• Two thumbs up
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ALLHAT
A new approach
"The system we have now, where
companies not only fund trials
but decide what the questions
are is not the right way to do it"
Doctors and patients want to know
which is the best choice among the
treatments that work?
Most companies avoid head-to-head
trials and try to game them even
when they agree
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Califf
ALLHAT
Honest broker
NIH or other agencies as an honest
broker is the model to pursue in the
future
"If a drug is a winner it ought to
prevail in a direct comparison
without the type of engineering
that can occur with interested
sponsors."
Topol
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ALLHAT
Pricing
The price of a drug should be a
function of how much it contributes
"The way it is now, people are
having to decide what to take and
what to buy without any
knowledge in many fields of
which one is really better."
In multiple sclerosis, for example,
there are 4 drugs and no one knows
which is really better
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Califf
ALLHAT
ALLHAT: Optimal first-step therapy
for hypertension
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
Thumbs up/Thumbs down – Feb 2003