Transcript Coaated stents: a new era

ANBP2
ANBP2: ACE inhibitors vs diuretics
for hypertension in the elderly
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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ANBP2
ANBP2: Trial design
Second Australian National Blood Pressure
Study
• 6083 elderly (65-84) hypertension
patients from 1594 family practices
• Randomized to ACE inhibitor or diuretic
(enalapril or hydrochlorothiazide
recommended but not mandated)
• Primary end point: any cardiovascular
event or death from any cause
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ANBP2
ANBP2: Results
Event
Hazard ratio*
95% CI
p
Primary end point
0.89
0.71-1.00
0.05
Primary end point
in men
0.83
0.71-0.97
0.02
Primary end point
in women
1.00
0.83-1.21
0.98
*ACE inhibitor vs diuretic
Wing LMH et al. N Engl J Med 2003;348:583-592.
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ANBP2
Questions raised
Did ALLHAT get the right answer?
Is ACE inhibitor really the first drug of
choice, not a diuretic?
Trial population almost exclusively
Caucasian
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Califf
ANBP2
Soft methodology
ALLHAT was large and rigorous and
the secondary end points clearly
favored chlorthalidone; this is
opposite
The methodology in ANBP2 is "loosey
goosey"
• Open label
• No restrictions on the drugs
Difficult to interpret soft methodology
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Topol
ANBP2
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
ANBP2
Effectiveness study
Is this a better model of how this
works in real practice?
ALLHAT restricted your choices of
second drug
This could be viewed as an
effectiveness study
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Califf
ANBP2
Proper trial design
A trial should be uniform, blinded, and
rigorous, even though it limits some
choices
"There's a choice of a very nonrestrictive approach . . . vs
one that is much rigorous, much
larger and much more
extrapolatable to a broader
population."
Topol
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ANBP2
Dead or alive
GUSTO I was unblinded, but the end
point was mortality
"I don't think blinding changes
death rate."
"A lot of things that are not dead or
alive can be influenced by the
unmasked nature of the drug."
Topol
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ANBP2
Biochemistry experiment
Masking can interfere with getting a
real-world result
"It might be a great biochemistry
experiment but it might not have
anything to do with what's going
to happen when you use the
drugs in practice."
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Califf
ANBP2
Unspecified drugs
Problems with ANBP2 methods
• Small numbers of patients
• Unblinded study drug with soft
end points
• Lack of uniformity of the drug
"How can you do a trial where you
don't even have those darn
drugs specified? That's really
weak."
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Topol
ANBP2
Race effect?
Trial
ALLHAT
(whites only)
ANBP2
Primary end point
Hazard
ratio*
Fatal CHD or nonfatal MI
0.94
Any CV event or allcause mortality
0.89
*ACE inhibitor vs diuretic
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ANBP2
The right answer?
Black patients with good kidney
function should be given a diuretic
and perhaps a calcium channel
blocker
White patients may be better off with
an ACE inhibitor or at least not
worse off
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Califf
ANBP2
Race effect
The differences may be affected by
race
Race isn't even reported in this trial
but presumably wasn't blinded
"There's a lot of things about this
report and the methodology that
make it surprising it would
surface in a high-impact
journal."
Topol
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ANBP2
The export of clinical trials?
Clinical trials are getting more and
more expensive and take a long
time to do
"It's been said that clinical trials will
be nonexistent in the US in the
near future. They will all be
exported to other countries
where they're not consumed by
all the regulatory burden."
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Califf
ANBP2
Burden of clinical research
The burden of clinical research is
dramatically increasing
• IRBs are overzealous
• HIPAA will make malfeasance a
criminal penalty
• Payments aren't keeping up
"We're just not going to have the
evidence for practice unless we
do more clinical research, not
less."
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Califf
ANBP2
Informed consent
Only 18% of patients in HERO-2
actually read the information sheet
before giving or refusing consent
CPR research was stopped due to
considerations like these; at least
AMI patients are awake
"It's certainly suboptimal with
somebody in the midst of pain
and fear to try to get a true
informed consent."
Topol
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ANBP2
Necessity of clinical trials
"[There is] increasing evidence that
unless we do the studies we
simply don't know what we're
talking about."
At the NIDDK they have done two
clinical trials
"No matter how much we believe
something based on 'experience'
life is pretty confounded."
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Califf
ANBP2
Human research
There is pressure to go through
extreme hurdles before you can do
research on humans
Research needs to regain public trust
"A lot of really great clinical trial
work . . . has come from inside the
US and hopefully it can be
sustained."
Topol
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ANBP2
Eastern Europe
Several large trials where most of the
enrollment is in Eastern Europe and
Russia
Can we trust the results if they are
done in a country that can't afford
the other forms of treatment
common in the US?
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Califf
ANBP2
Comparing medical systems
It can be hard to determine whether
the difference in a trial is due to the
drug or the medical system of the
countries the studies are performed
in
"You want to have a trial that's
global but truly representative."
Topol
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ANBP2
Dietary supplements
Dietary supplement sales: $17.8
billion, 3 billion doses consumed by
12 to 17 million Americans (2001)
Ephedra accounted for 0.82% of US
herbal supplement sales but 62% of
all herb-related reports to US poison
control centers (2001)
"I still don't understand, why is
ephedra on the market? There's
nothing good about this drug."
Topol
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ANBP2
Dietary supplements
Patients in clinic request coenzyme
Q10 to replace their statin
None of these supplements are FDA
reviewed but they can criticize
statins, which have more evidence
supporting it than almost any other
therapeutic in cardiovascular
medicine
"This befuddles me how this can
keep continuing."
Topol
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ANBP2
Lack of regulation
FDA hasn't been allowed to regulate
dietary supplements
Supplements are presumed safe until
proven otherwise
Drugs are not presumed safe until they
are proven to be
"It's your congress at work."
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Califf
ANBP2
Alternative medicine
Andrew Weil was pushing natural
estrogens after the dangers of
hormone replacement therapy
became known
Alternative-medicine proponents
without evidence hurt clinical
research by blurring the boundaries
of good and bad research
Topol
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ANBP2
Approaches to hypertension
In light of ALLHAT and ANBP2
• Blood pressure is inadequately
treated
• Diuretic is probably the drug to
start with
• ACE inhibitors do look good
• Amlodipine is not as bad as some
people thought it was and may
even be pretty good
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Califf
ANBP2
Furthering confusion
Amlodipine is still questionable due to
the heart failure excess
The methodological problems with
ANBP2 add to the confusion
We need a standard, rigorous
approach for important clinical trials
In elderly patients of Caucasian origin
ACE inhibitors might not be so bad
Topol
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ANBP2
Thumbs
Topol: "I would give it two thumbs
down because the methodology was
very poor."
• Two thumbs down
Califf: "We need effectiveness trials
and they create good discussions."
• One thumb up
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ANBP2
ANBP2: ACE inhibitors vs diuretics
for hypertension in the elderly
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 – Mar 2003