Transcript Coaated stents: a new era

ALLHAT
ALLHAT and ALLHAT-LLT
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Christopher Cannon MD
Cardiologist
Brigham and Women's Hospital
Boston, MA
James Ferguson MD
Associate Director, Cardiology
St Luke's Episcopal Hospital and Texas Heart Institute
Houston, TX
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Heartbeat – Jan 2003
Brooklyn, NY
ALLHAT
ALLHAT and ALLHAT-LLT
Special Guest Commentator
Thomas G Pickering MD, PhD
Director, Integrative and Behavioral Cardiovascular Health
Program And Hypertension Program
Mount Sinai Medical Center
New York, NY
Heartbeat – Jan 2003
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
Heartbeat
– Jan (up
2003to 8 yrs).
study
ALLHAT
ALLHAT: Trial design
• 33 357 patients age >55 with hypertension
and 1 additional risk factor
• Randomized to:
chlorthalidone (12.5 mg to 25 mg/day,
n=15 255)
amlodipine (2.5 mg to 10 mg/day,
n=9048)
lisinopril (10 mg to 40 mg/day, n=9054)
• Primary end point: fatal CHD or nonfatal MI
Heartbeat – Jan 2003
ALLHAT
ALLHAT: Primary end point
Chlorthalidone
Lisinopril
Amlodipine
12.0
Events (%)
10.0
8.0
6.0
4.0
2.0
0.0
Heartbeat – Jan 2003
JAMA 2002; 288:2981-2997
ALLHAT
Secondary outcomes: Amlodipine
vs chlorthalidone
End
point
Amlodipine Chlorthalidone
(%)
(%)
6-year
rate of
heart
failure
10.2
7.7
Relative
risk
p
1.38
(1.251.52)
<0.001
JAMA 2002; 288:2981-2997
Heartbeat – Jan 2003
ALLHAT
Summary
Why did diuretics do so well in this
population, when we've all been talking
about how great the ACE inhibitors are?
How do we unravel this surprising finding?
Heartbeat – Jan 2003
Fuster
ALLHAT
A negative study
"I was frustrated by the authors
immediately portraying this paper in
public policy and economic terms."
"I am by no means convinced that this
study is anything other than what you
might normally call a negative study."
"I'm not convinced the discrepancies
between the drugs are as
obviously apparent as claimed."
Heartbeat – Jan 2003
Weber
ALLHAT
ALLHAT: Blood pressure
Systolic BP (mm Hg)
Chlorthalidone
Lisinopril
Amlodipine
150
145
140
135
130
125
0
1
2
3
4
5
Years
Heartbeat – Jan 2003
JAMA 2002; 288:2981-2997
ALLHAT
Heart-failure protection
"I was astonished with the heart-failure
result."
It seems an ACE inhibitor would be a
superior protector against heart
failure
Could the chlorthalidone be masking the
symptoms of heart failure and
resulting in missed diagnoses?
Heartbeat – Jan 2003
Weber
ALLHAT
Blood-pressure effect
It is possible the blood-pressure
difference explains some, if not most,
of the final results
There was a consistent difference
throughout the trial
ACE inhibitors have been shown to be
more effective in younger
patients, and the age of the
trial participants may be a
factor in ALLHAT
Pickering
Heartbeat – Jan 2003
ALLHAT
Blood-pressure difference
Can the blood pressure have had
significant impact when the difference
was so small?
Blood-pressure difference compared with
chlorthalidone
Amlodipine:
+0.8 mm Hg
Lisinopril:
+2.0 mm Hg
Heartbeat – Jan 2003
Fuster
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
Heartbeat – Jan 2003
JAMA 2002; 288:2981-2997
ALLHAT
ALLHAT: Masking heart failure
It is possible the diuretics were masking
some of the clinical manifestations of
heart failure
"I don't think that [ALLHAT] means that
we should throw out all the new forms
of therapy and go back to treating
everybody with diuretics."
Heartbeat – Jan 2003
Ferguson
ALLHAT
ALLHAT: Understanding the biology
"Is it the blood-pressure control or is it
the specific agents?"
We have confounding results and don't
have the absolute answer right now
We haven't had a chance to examine all
the different subgroups yet
Heartbeat – Jan 2003
Ferguson
ALLHAT
ALLHAT: Fundamental principles
"We've been going along fat, dumb, and
happy thinking we've got all these
great new forms of therapy and they're
so much better than what we had
before. And now we've got to
reexamine that."
We need to apply the principles of risk
stratification to the world of
hypertension
Heartbeat – Jan 2003
Ferguson
ALLHAT
ALLHAT: A surprise
"I think we were all somewhat
surprised."
Consensus of meta-analyses was CCBs
are better at preventing stroke, while
ACE inhibitors are better at preventing
coronary events when compared to
standard diuretic and beta-blocker
treatment
Heartbeat – Jan 2003
Pickering
ALLHAT
ALLHAT: Elderly population
ALLHAT had a relatively elderly
population:
mean age:
67 years
57% of patients >65
We don't have as many comparative trials
in the elderly
Heartbeat – Jan 2003
Pickering
ALLHAT
ALLHAT: Heart failure
Increased heart failure was a factor
involved in stopping the doxazosin
arm of ALLHAT
"It may be that the diuretic tends to
reduce sodium retention whereas
some of these agents may be
associated with sodium retention if
not given in combination with a
diuretic."
Heartbeat – Jan 2003
Pickering
ALLHAT
HOPE: Primary end points
Ramipril
Placebo
18
Events (%)
16
14
12
10
8
6
4
2
0
CV death
Heartbeat – Jan 2003
MI
Stroke
Combined
N Engl J Med 2000; 342(3):145-153
ALLHAT
African American population
There seems to be an inconsistency
between HOPE and ALLHAT concerning
ACE inhibitors
ALLHAT was designed to have a large
black population (35%) in the study
ACE inhibitors may be less effective in
this population
Heartbeat – Jan 2003
Weber
ALLHAT
Overinterpreting the findings?
30% to 40% of the benefit seen in HOPE
may come from lowering blood
pressure
Can argue that in the white cohort in
ALLHAT, ACE inhibitors may have
reduced coronary events 5% to 8%
once blood pressure is factored in
"I am rather concerned that the
authors of the study [ALLHAT]
have perhaps overinterpreted
their own findings"
Heartbeat – Jan 2003
Weber
ALLHAT
Biochemical changes
Past studies with diuretics suggested that
one of the problems with the drug was
an effect on elements like fasting
glucose, potassium, etc
These may increase risk for people with
hypertension
Does ALLHAT tell us we should stop
worrying so much about these
things?
Heartbeat – Jan 2003
Fuster
ALLHAT
New-onset diabetes
In SHEP, diabetics did well on
chlorthalidone
Beta blockers may help prevent newonset diabetes
ACE inhibitors have also been linked to
prevention of new-onset diabetes
Heartbeat – Jan 2003
Pickering
ALLHAT
ALLHAT: Fasting glucose levels
Fasting glucose >126
mg/dL (%)
Chlorthalidone
Lisinopril
Amlodipine
35
30
25
20
15
10
5
0
Heartbeat – Jan 2003
Baseline
2 years
4 years
JAMA 2002; 288:2981-2997
ALLHAT
Three patients
Which would be the first drug of choice?
Patient 1: Age 65; BP 170/100;
no evidence of atherosclerotic
disease
Patient 2: Age 65; BP 170/100;
previous MI, good LVF
Patient 3: Age 65; BP 170/100;
previous stroke
Heartbeat – Jan 2003
ALLHAT
First patient
Patient 1: Age 65; BP 170/100;
no evidence of atherosclerotic
disease
Patient 2: Age 65; BP 170/100;
previous MI, good LVF
Patient 3: Age 65; BP 170/100;
previous stroke
Heartbeat – Jan 2003
ALLHAT
First patient: First drug
Weber: Start with calcium channel
blocker, maybe a diuretic in a black
patient
Pickering: Diuretic
Ferguson: Diuretic
Cannon: Diuretic, maybe a generic ACE
inhibitor
Fuster: ACE inhibitor in the past–not sure
now
Heartbeat – Jan 2003
ALLHAT
Digesting ALLHAT
We must teach our colleagues that the
last word is not yet in on all this
"This is a very complicated story,
ALLHAT, we're going to have to take a
few months to fully digest it."
Heartbeat – Jan 2003
Weber
ALLHAT
Second patient
Patient 1: Age 65; BP 170/100;
no evidence of atherosclerotic
disease
Patient 2: Age 65; BP 170/100;
previous MI, good LVF
Patient 3: Age 65; BP 170/100;
previous stroke
Heartbeat – Jan 2003
ALLHAT
Second patient: First drug
Weber: ACE inhibitor
Pickering: Beta blocker
Ferguson: ACE inhibitor
Cannon: Beta blocker, followed by ACE
inhibitor
Fuster: ACE inhibitor
Heartbeat – Jan 2003
ALLHAT
Third patient
Patient 1: Age 65; BP 170/100;
no evidence of atherosclerotic
disease
Patient 2: Age 65; BP 170/100;
previous MI, good LVF
Patient 3: Age 65; BP 170/100;
previous stroke
Heartbeat – Jan 2003
ALLHAT
Third patient: First drug
According to PROGRESS study, you should
use a combination of ACE inhibitor and
a diuretic
Likely to start with diuretic for older
patient and ACE inhibitor for younger,
but will end up with both
Heartbeat – Jan 2003
Pickering
ALLHAT
Third patient: First drug
This patient is a quandary right now,
having both manifest atherosclerotic
disease and hypertension
I am still biased toward ACE inhibitors and
will make that the first line of therapy
Cannot lose sight of the underlying
atherosclerotic disease
Heartbeat – Jan 2003
Ferguson
ALLHAT
Third patient: First drug
I want to finish up with both ACE inhibitor
and a diuretic (PROGRESS trial) so it
doesn't matter which I start with
"Someone who comes in with 170
systolic, you aren't going to get him
down to 140 with 1 drug anyway."
We all seem likely to end up with an
ACE inhibitor and a diuretic as a
combination
Heartbeat – Jan 2003
Weber
ALLHAT
Third patient: First drug
Start with an ACE inhibitor for the
vascular disease risk and then titrate
to blood pressure with diuretic as a
follow-up drug
Heartbeat – Jan 2003
Cannon
ALLHAT
Drug choice based on patient
An ACE inhibitor followed by a diuretic
Seems that for a patient age 65 with
• No manifestation of disease–start
with a diuretic
• CAD with good VF–ACE inhibitor
• After a stroke–combination
of ACE inhibitor and diuretic
Heartbeat – Jan 2003
Fuster
ALLHAT
Implications of ALLHAT
ALLHAT suggested that all of these drugs
are similar in their effect
"Tragically, ALLHAT never examined the
sorts of combinations that we use."
ALLHAT is complicated by the fact the
patients weren't treated in the way
they would be in the real world
Heartbeat – Jan 2003
Weber
ALLHAT
ALLHAT mortality
.3
.25
.2
HR (95% CI)
p
A/C
0.96 (0.89-1.02)
0.20
L/C
1.00 (0.94-1.08)
0.90
Chlorthalidone
Amlodipine
Lisinopril
.15
.1
.05
0
0
Heartbeat – Jan 2003
1
2
3
4
Years to death
5
6
7
ALLHAT trial site
ALLHAT
ALLHAT-LLT: Trial design
• 10 355 patients age >55 with hypertension
and 1 additional risk factor and moderate
hypercholesterolemia
• Randomized to:
pravastatin (40 mg/day, n=15 255)
usual care
• Primary end point: all-cause mortality
Heartbeat – Jan 2003
ALLHAT
ALLHAT-LLT: Primary results
Pravastatin
Usual care
6-year event rate/
100 patients
16
14
12
10
8
6
4
2
0
Heartbeat – Jan 2003
Mortality
CHD and nonfatal MI
JAMA 2002; 288:2998-3007
ALLHAT
HPS: Mortality results
Simvastatin
Placebo
Event rate (%)
16
14
12
10
8
6
4
2
0
All-cause mortality
Heartbeat – Jan 2003
Vascular death
Lancet 2002; 360:7-22
ALLHAT
ALLHAT-LLT: Statin use
Statin arm
Usual care arm
90
% on statin
80
70
60
50
40
30
20
10
0
Heartbeat – Jan 2003
2 years
4 years
6 years
JAMA 2002; 288:2998-3007
ALLHAT
ALLHAT-LLT: Evolving standard of care
"We've been going along thinking that the
statins are the answer to all of our
atherosclerotic disease problems, and
they're not."
If usual standard of care means 30%
are on statins anyway, it's hard to
improve on that with a statin
Heartbeat – Jan 2003
Ferguson
ALLHAT
ALLHAT-LLT: Open label
ALLHAT-LLT was not a double-blind trial,
it was open-label
Lots of dropouts
(22.6% of statin arm came off their
drug over the course of the trial)
The big difference with other statin trials
lies in the study design
Heartbeat – Jan 2003
Cannon
ALLHAT
ALLHAT-LLT: Designing clean studies
Must construct clean, well-designed
studies that can give meaningful
results even in the face of an
improving standard of care
ALLHAT-LLT was also underpowered due
to lack of enrollment
Heartbeat – Jan 2003
Cannon
ALLHAT
ALLHAT-LLT: Crossovers
It may become more difficult to see
differences in the future, the real
danger is crossovers
An unblinded trial makes it much easier to
use the study drug as part of usual care
Heartbeat – Jan 2003
Fuster
ALLHAT
ALLHAT-LLT: LDL-C
LDL-C in mg/dL
150
* Percent decrease from baseline.
140
7% *
130
11%
Usual care
120
23%
110
Pravastatin
28%
100
0
Heartbeat – Jan 2003
16%
2
Year of blood draw
4
30%
6
ALLHAT
Summary: ALLHAT
In a hypertensive population, a diuretic was
as good as the use of amlodipine and
lisonipril
"Diuretics may not be as bad as I thought."
The results may be due in part to bloodpressure effects
Heartbeat – Jan 2003
Fuster
ALLHAT
Summary: ALLHAT-LLT
"It's not a good study."
There was a lot of crossover, and that makes
it difficult to draw conclusions
It hasn't changed my opinion on statins
Heartbeat – Jan 2003
Fuster
ALLHAT
Final word: Ferguson
In both studies our preconceived notions
were wrong
The studies reinforce which mechanisms we
should be targeting
• ALLHAT: focus on blood pressure in
hypertensive patients
• ALLHAT-LLT: should still be
treating cholesterol is a
priority
Heartbeat – Jan 2003
Ferguson
ALLHAT
Final word: Pickering
ALLHAT makes me think people should be
using diuretics more
• Current trends show diuretics being
used less and less
ALLHAT-LLT won't change the way I use
statins in my practice
Heartbeat – Jan 2003
Pickering
ALLHAT
Final word: Cannon
"One will be much more apt to turn to
diuretics and include them as part of
combination therapy."
The lesson from LLT is that one wants to do a
clean trial as the way to examine if
something is beneficial
Heartbeat – Jan 2003
Cannon
ALLHAT
Next program
AHA 2002 Part 2
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Christopher Cannon MD
Cardiologist
Brigham and Women's Hospital
Boston, MA
James Ferguson MD
Associate Director, Cardiology
St Luke's Episcopal Hospital and Texas Heart Institute
Houston, TX
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Heartbeat – Jan 2003
Brooklyn, NY