Transcript Califf - Medscape

Direct coronary intervention for MI
Chronic therapy of cardiovascular
disease
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, Ohio
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, North Carolina
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Direct coronary intervention for MI
LIFE and OVERTURE/OCTAVE
LIFE
• Losartan Intervention For Endpoint
Reduction in Hypertension
OVERTURE
• Omapatrilat Versus Enalapril
Randomized Trial of Utility in Reducing
Events
OCTAVE
• Omapatrilat Cardiovascular Treatment
Assessment Versus Enalapril
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Direct coronary intervention for MI
LIFE: Inclusion criteria
Atenolol vs Losartan
• 9193 patients
• Age 55-80 years
• Previously treated or untreated hypertension
• Systolic BP 160-200 mm Hg or diastolic BP 95115 mm Hg
• ECG LVH
• Primary composite endpoint of cardiovascular
morbidity and mortality, defined as stroke, MI,
or cardiovascular death
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Direct coronary intervention for MI
LIFE: Event rate
Losartan
14%
12%
Atenolol
p=0.021
11% 13%
10%
p=0.491
8%
6%
p=0.001
5%
7%
4%
4%
p=0.206
4%
4%
5%
2%
0%
Composite
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MI
Stroke
Death
ACC 2002
Direct coronary intervention for MI
LIFE: Implications
Beta-blockade had been on such a
high pedestal and now this puts the
sartans in a whole other light
"I'm a little bit stunned about the
results, not knowing exactly how
to change practice."
Topol
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Direct coronary intervention for MI
LIFE: Expectations
Investigators expected the primary
beneficial effect to be on the heart
as a result of the animal data
"The trial was done extremely well
and measured the right things,
but the result was unexpected.
The benefit was in the direction
the investigators had postulated
but […] not for the outcome
reason they had thought."
Califf
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Direct coronary intervention for MI
LIFE: Head-to-head clinical trials
As we get head-to-head trials,
interpreting them will be very
complicated.
"The Evidence-Based Medicine Mafia
[…] has been extremely high on betablockers […], and I haven't lost any
enthusiasm for beta-blockers from this
trial but I've gained a lot of respect for
ARBs and their potential to produce
benefit."
Califf
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Direct coronary intervention for MI
LIFE: Blood pressure follow-up (4.8
years)
180
Atenolol
Losartan
160
Atenolol 145.4 mm Hg
Systolic
mm Hg
140
Losartan 144.1 mm Hg
120
100
Losartan 81.3 mm Hg
80
Diastolic
Atenolol 80.9 mm Hg
60
40
0
6
12
18
24 30 36
Study Month
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42
48
54
B Dahlof et al. Lancet 2002;359:995-1003
Direct coronary intervention for MI
LIFE: Blood pressure
The real role of blood pressure can
be difficult to determine
We don't have any information
about the pulse wave, which is
potentially important
"Nor do we have quite yet the full
sense of the distribution of blood
pressure effects in the
population or across time."
Califf
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Direct coronary intervention for MI
LIFE: How generalizable?
This trial had an overwhelmingly white
patient population. Can we generalize
to the more heterogeneous population
you would find in general practice?
Topol
"I wouldn't abandon the fundamental
principles that you treat blood
pressure with a low-dose thiozide
diuretic and in someone who has a risk
of MI [ …] you err toward beta-blocker
and an ACE inhibitor."
Califf
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Direct coronary intervention for MI
LIFE: Not cheap
These are exciting new drugs with
real potential but they are not cheap
"For people who can take an ACE
inhibitor and who don't cough
and feel fine and can get them
at a lower price, I'm all for that."
Califf
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Direct coronary intervention for MI
LIFE: Stroke belt
Source: CDC
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Direct coronary intervention for MI
LIFE: Applying the data
There could be a genetic component
to the stroke belt, making the LIFE
data difficult to generalize
"I've been using ARBs a fair
amount, this will make me feel
even better about using them
more often but to make a radical
change in the fundamental
approach to blood pressure
based on one trial, I think would
be a mistake."
Califf
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Direct coronary intervention for MI
LIFE: New onset diabetes
Proportion of patients with first event
(%)
8
Intention-to-Treat
7
Atenolol
6
Losartan
5
4
3
2
Adjusted Risk Reduction 25%, p=0.001
1
0
0
6
12
18
24
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30
36
42
48
54
60
66
Study Month
Dahlof et al. Lancet 2002;359:995-1003
Direct coronary intervention for MI
LIFE: Lifestyle changes
Walking 4 times a week for 30
minutes a day would be more
effective than losartan
"But the changes in lifestyle are
hard to come by. Unfortunately,
our society relies too much on
some pill and potion rather than
the discipline of exercise and
diet."
Topol
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Direct coronary intervention for MI
LIFE: Start with ARBs for hypertension?
Maybe we could start with ACE inhibitors
or ARBs in a newly diagnosed
hypertensive patient
• Patients successfully on beta-blockers
shouldn't be switched
• These patients are hypertensives with
serious left-ventricular hypertrophy
and have already tried diuretic therapy
and failed
• This may all be rendered moot by
advances in genomics, proteonomics,
and tailored therapy
Topol
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Direct coronary intervention for MI
LIFE: Multiple drugs
The average person with real systolic
hypertension will require 2.6 drugs at
maximal FDA levels to get their pressure
below 140
• The ARB option is well-tolerated,
making it very attractive
• ALLHAT does not include ARBs, but
should give us the first real evidence
about what drug you should start with
Califf
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Direct coronary intervention for MI
LIFE: The pocketbook
We have to balance what we need to
do and the pocketbook
Economic factors get in the way of
proper treatment
"It's difficult to take someone who
feels fine and has not had a
stroke and convince them that
they should take not one, and
not two, but three drugs that
cost 2 or 3 bucks a day apiece."
Califf
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Direct coronary intervention for MI
LIFE: DPP
Incidence of type 2 diabetes
Lifestyle modification
Metformin
12.0
Placebo
11.0
10.0
7.8
8.0
6.0
4.8
4.0
2.0
0.0
Cases per 1000 person years
Diabetes Prevention Program Research Group.
N Engl J Med 2002;346(6):393-403
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Direct coronary intervention for MI
LIFE: Obesity
US population with BMI > 30
20%
15%
17.9%
18.9%
19.8%
15.3%
12.0%
10%
5%
0%
Year
1991
1995
1998
1999
2000
Source: CDC
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Direct coronary intervention for MI
LIFE: NAVIGATOR
Nateglinide And Valsartan in Impaired
Glucose Tolerance Outcomes Research
Nateglinide (60mg before main meals)
vs valsartan (160mg daily) vs placebo
• > 60 000 patients screened for
impaired glucose tolerance (IGT)
• 7500 subjects to be enrolled
• 600-800 centers in 40 countries
• Age > 50 with at least 1 CV risk factor
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Direct coronary intervention for MI
LIFE: Outpatient cardiology
Outpatient cardiology is really a metabolic
clinic; we're seeing the classic lifestyle
problems
It is hoped we can integrate the
diabetologists' understanding of glucose
management
"We're going to see much attention
to focused metabolic clinics run
by major cardiovascular centers."
Califf
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Direct coronary intervention for MI
LIFE: Marinating the blood vessels
Jay Cohn advocates we abandon
measuring blood pressure; we
should focus on getting patients on
effective doses of drugs
"The concept of marinating blood
vessels with the right doses of
drugs as opposed to trying to hit
these targets, which have never
really been proven to be correct,
might be the way to go."
Califf
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Direct coronary intervention for MI
LIFE: Diabetes prevention
Diabetes prevention has been seen
in 3 rigorous trials; there is a theme
"I think it's more than just
marinating the blood vessels.
There must be an antiinflammatory effect that's
afforded by working on this
neurohumoral axis of ACE and
ARBs and I think it's
fascinating."
Topol
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Direct coronary intervention for MI
Topol: 2 thumbs up for LIFE
"Very provocative trial. I love to
see trials where you get a
surprise finding, shake the
bushes. It's good for the field."
"I hope this one does get the
interest it deserves in the
cardiovascular community."
Topol
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Direct coronary intervention for MI
OVERTURE and OCTAVE
"[OVERTURE and OCTAVE were]
supposed to be the big trials to
validate omapatrilat as a
cornerstone of heart failure and
hypertension therapy. And I
guess that didn't exactly turn out
to be the case."
Topol
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Direct coronary intervention for MI
OVERTURE: Background
Omapatrilat vs enalapril for heart failure
• An ACE-NEP inhibitor (works through
angiotension converting enzyme and
the neutral endopeptidase)
• More effective than straight ACE
inhibitor in lowering systolic blood
pressure
• Two phase 2 trials both trended to
mortality reduction
Califf
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Direct coronary intervention for MI
OVERTURE: Event rate
Omapatrilat
Enalapril
HR=0.91
p=0.024
1400
HR=0.93
p=0.187
1200
Events
1000
HR=0.93
p=0.233
800
HR=0.94
p=0.339
600
400
200
0
Composite
CV
death/hospital
Packer et al. ACC 51st Annual Scientific Session.
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All-cause
mortality
Death/CHF
hospitalization*
*primary endpoint
Direct coronary intervention for MI
OVERTURE: Negative perception
Most portrayals seem overly negative
"If your expectation was that
omapatrilat was going to have to
be way better than ACE inhibitor
then it's definitely a negative. If
your expectation was that we could
make a modest incremental
improvement, it may not have
knocked omapatrilat out of the
box, at least in the field of heart
failure."
Califf
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Direct coronary intervention for MI
OVERTURE: Event rate
HR=0.91
p=0.024
1250
1000
In a head-to-head trial,
how do you know either is
better than placebo?
If you use the ACE inhibitor
mortality trial end point,
you get a nominally
significant result
750
500
250
0
Califf
CV
death/hospital
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Direct coronary intervention for MI
OVERTURE: Adverse events
Event
enalapril
omapatrilat
CHF
25.6%
22.6%
Hypotension
11.5%
19.5%
Dizziness
13.9%
19.4%
Impaired renal function
3.6%
2.3%
Angioedema
0.5%
0.8%
Packer et al. ACC 51st Annual Scientific Session.
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Direct coronary intervention for MI
OVERTURE: Shades of benefit
ACE inhibitors are generic now,
making for an inexpensive reference
standard
"You have some shades of benefit
but it’s going to be an expensive
alternative and the benefit is not
assured. […] And angioedema is
not exactly a nuisance, it's lifethreatening."
Topol
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Direct coronary intervention for MI
OVERTURE: Interpreting the data
"I think fundamentally, the most
important point about the
pragmatic interpretation of the
data is that to replace an ACE
inhibitor, you've got to really
beat it. And this trial did not beat
it."
Califf
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Direct coronary intervention for MI
OVERTURE: The future
"For those more interested in research
and its future implications, does this
mean the death of the ACE/NEP
combination? I don't think so. Yet."
Califf
"Unfortunately, though, for the
expectations of the drug, which were
far greater than validating it as an
alternative, it was demonstrating its
superiority, and it was far from that."
Califf
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Direct coronary intervention for MI
OVERTURE: Before and after
"Going into the ACC I would have thought
most people would say, ARBs, that's a
yawner. You know, they're nice to have
around, but so what? ACE/NEP, that's
where the action is."
"Now after the ACC we say, Jeez, ARBs,
they're phenomenal, and the ACE/NEP
– well, you know, you've got a drug
that's maybe a little better but has the
same side effects or worse."
Califf
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Direct coronary intervention for MI
OVERTURE: Benefit of sartans
"This whole class has been kind of
clouded by lack of data showing
precise benefits."
"You're right, I think that was one
of the major themes that came
out of this meeting [is that]
there were some big benefits
that I guess were not fully
expected."
Topol
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Direct coronary intervention for MI
OCTAVE: Risk of angioedema
Event
enalapril
omapatrilat
All patients
0.68%
2.17%
Blacks
1.62%
5.54%
Nonblacks
0.55%
1.78%
Smokers
0.81%
3.93%
Nonsmokers
0.66%
1.79%
The OCTAVE Study Group. ACC 51st Annual Scientific Session.
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Direct coronary intervention for MI
OCTAVE: Pharmacogenetics
"This could be a great drug for
managing blood pressure if you
could just screen out the people
who were gonna be getting
angioedema. And that could be
easily done by a SNP analysis."
"This could be one of the earliest
applications of pharmacogenetics."
Topol
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Direct coronary intervention for MI
OCTAVE: At-risk patients
We need a way to identify the population at
high-risk for angioedema
"Those who look on the rosy side say, 'Well,
there's not been a death yet due to
angioedema in the omaptrilat
experience.' But the setting of a clinical
trial is very different from the setting in
a community health clinic where people
with hypertension are being treated
and sent out there."
Califf
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Direct coronary intervention for MI
OCTAVE: Good blood pressure response
No one has seen the full data from
OCTAVE
• Blood pressure response was better
with omapatrilat
• If blood pressure effects are important
in hypertension, this could be of benefit
for those with the worst levels of
systolic hypertension
Califf
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Direct coronary intervention for MI
OCTAVE: How important is BP
"I'm uncertain how much of it is
really a pressure effect."
A meta-analysis by Curt Furberg
implies that 50% of the benefit of
any hypertensive drug is based
purely on the blood pressure
lowering
Califf
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Direct coronary intervention for MI
OCTAVE: Benefits of low BP
I can't argue there is no benefit to
lowering blood pressure per se
"I can bleed you into a trash can
and lower your blood pressure
and it doesn't mean its good for
you."
"You've got to consider the full
effects of a drug you're going to
give people."
Califf
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Direct coronary intervention for MI
OCTAVE: Screening
Omapatrilat is a potent drug, but it has
a relatively infrequent serious side
effect we could screen out
"Perhaps some day we'll see broad
application but in a
pharmacogenetic way. It only
takes a few dollars to run a
polymorphism and it could mean a
very effective therapy in those
patients who are not at risk."
Topol
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Direct coronary intervention for MI
OCTAVE: Applying polymorphisms
"How are you going to get doctors
to run a polymorphism test when
they can't even give the drug in
the first place?"
Califf
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Direct coronary intervention for MI
OCTAVE: Genetics in cancer
Cancer specialists are ahead of
cardiovascular specialists in using
pharmacogenetics
• Talking about specific genetic linkages
used to design therapies
• Omapatrilat is an attractive case
because we know the pathway and it is
easy to find SNPs in particular genes
• By next year, it should be a "nobrainer"
Topol
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Direct coronary intervention for MI
OCTAVE: The big issue
Getting the drugs to the people
who benefit the most is the big
issue
"Oftentimes I'm afraid that
people just assume that
operationalizing a concept
is automatic. We've got a lot
of work to do."
Califf
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