Download ESC 2003

ESC 2003
ESC 2003:
Confirming knowledge
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 – Sept 2003
Brooklyn, NY
ESC 2003
Topics
Use of an oral antithrombin post MI
ESTEEM
Role of an ARB in cardiac failure
CHARM
ACE inhibitor for chronic stable CAD
EUROPA
Heartbeat – Sept 2003
ESC 2003
ESTEEM
Oral ximelagatran for secondary prophylaxis after
myocardial infarction (Lancet 2003; 362: 789–97)
• 1883 patients with recent MI (<14 days)
• Ximelagatran (24, 36, 48, or 60 mg twice daily)
and aspirin (160 mg once daily) vs aspirin alone
• Primary end point: all-cause death, nonfatal MI,
and severe recurrent ischemia
• Six-month follow-up
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Results
Placebo
Ximelagatran
16
Events (%)
14
12
10
8
6
4
2
0
24 mg
36 mg
48 mg
60 mg
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
SPORTIF III: Primary events
Ximelagatran
2.5
p=NS
Warfarin
p=0.018
Events (%)
2.0
1.5
1.0
0.5
0.0
Heartbeat – Sept 2003
Intention-to-treat
On-treatment
ACC 2003
ESC 2003
ESTEEM: Well-done trial
A properly sized dose-ranging trial
It supports the notion that
anticoagulation plus aspirin is better
than aspirin alone
"Just aspirin is no longer the optimal
long-term management strategy."
Heartbeat – Sept 2003
Cannon
ESC 2003
ESTEEM: Raising questions
This moves beyond the level of previous
studies that showed long-term
secondary-prevention benefit
Ximelagatran gives us something at least
as good as warfarin therapy, without
all the downside
There was no dose effect seen in the
doses used in the study
Heartbeat – Sept 2003
Ferguson
ESC 2003
ESTEEM: Liver function
Placebo
Ximelagatran (all doses combined)
Events (%)
7
6
5
4
3
2
1
0
2-3x
3-5x
>5x
Peak alanine transaminase
(upper limit)
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Not surprised
"I could say I am pleased and not
particularly surprised."
It was already known to compare well to
warfarin in efficacy while being easier
to use
How does this compare with using two
antiplatelet drugs together?
Heartbeat – Sept 2003
Weber
ESC 2003
ESTEEM: Warfarin + aspirin
Warfarin + aspirin is similar to aspirin +
clopidogrel
• We need to compare these
strategies side by side
"One gets a sense that the data are
actually very similar in terms of the
combinations of end points."
Heartbeat – Sept 2003
Fuster
ESC 2003
ESTEEM: What do we choose?
"This is the big question as we have more
and more options available: which to
choose?"
ESTEEM is a phase 2, hypothesisgenerating, study
Ximelagatran is not yet ready for use in
this patient population
Heartbeat – Sept 2003
Cannon
ESC 2003
ESTEEM: Stents
Patients with stents have an absolute
indication for clopidogrel
The next question will be safety and
tolerability of clopidogrel, aspirin, and
ximelagatran together
"Lots of testing and trial work needs to be
done."
Heartbeat – Sept 2003
Cannon
ESC 2003
ESTEEM: Results
Placebo
Ximelagatran
16
Events (%)
14
12
10
8
6
4
2
0
24 mg
36 mg
48 mg
60 mg
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Major bleeding
Placebo
Ximelagatran
Major bleeding (%)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
24 mg
36 mg
48 mg
60 mg
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Total bleeding
Placebo
Ximelagatran
Total bleeding (%)
25.0
20.0
15.0
10.0
5.0
0.0
24 mg
36 mg
48 mg
60 mg
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Dosing questions
As you push the dose, you could expect
more bleeding issues
"You go with the most effective drug with
the least number of complications."
All the doses seem to be above a threshold
for efficacy
Bleeding is comparable to warfarin,
and so ximelagatran still works
as a replacement
Heartbeat – Sept 2003
Ferguson
ESC 2003
ESTEEM: Alanine transaminase
Placebo
Ximelagatran
>5x upper limit of
normal (%)
9
8
7
6
5
4
3
2
1
0
24 mg
36 mg
48 mg
60 mg
Lancet 2003; 362: 789–97
Heartbeat – Sept 2003
ESC 2003
ESTEEM: Liver enzyme tests
"I'd rather not see [a liver enzyme
increase], but at the same time it isn't
really worrying me too much."
Threefold increases in ALT aren't unusual;
the FDA seems to get worried around
an increase of six- to eightfold normal
The increase seems to be an earlywarning signal
Heartbeat – Sept 2003
Weber
ESC 2003
ESTEEM: Dose response
Dose-response curve appears flat
"Did they get the dose-response curve in
completely the wrong place and
instead of looking at 24 mg and above,
should they have been looking at 6
and 12 and 24?"
Would different doses have produced
comparable efficacy but with a
better side-effect profile?
Heartbeat – Sept 2003
Weber
ESC 2003
ESTEEM: Administering the drug
GP IIb/IIIa inhibitors
• Fantastic given parenterally
• Terrible given orally
Thrombin inhibitors
• Question mark given parenterally
• Fantastic given orally
Heartbeat – Sept 2003
Fuster
ESC 2003
ESTEEM: Dosing
Oral GP IIb/IIIa inhibitors are hard to
dose properly
• The very high level of inhibition
needed is not tolerated long term
One can titrate oral thrombin inhibitors to
the right dose
• Dose is well tolerated in the
long-term
Heartbeat – Sept 2003
Cannon
ESC 2003
ESTEEM: Excitement level
"I am very excited, actually, [by the
results of the ESTEEM trial]."
Are you all only moderately excited
because SPORTIF III has already
convinced you and this is just SPORTIF
III in the arterial system?
Heartbeat – Sept 2003
Fuster
ESC 2003
ESTEEM: Cannon summary
"I'm extremely excited [about
ximelagatran] on the venous side,
because we desperately need
therapies there."
In the arterial system, we already have
other theories that are effective
Adding options is good, but exactly
where it fits in is still unknown
Heartbeat – Sept 2003
Cannon
ESC 2003
ESTEEM: Ferguson summary
SPORTIF III presented an alternative to
warfarin therapy and where warfarin
works, an alternative to warfarin will
work
"I continue to be excited about the
opportunity to ultimately replace
warfarin with a better drug."
Heartbeat – Sept 2003
Ferguson
ESC 2003
ESTEEM: Weber summary
ESTEEM is a nice alternative to good
therapies we already had
SPORTIF III presented a breakthrough
for treatment of atrial fibrillation with
antithrombin therapy
"This is an exciting study, but perhaps
doesn't have quite the impact
that we've seen earlier with the
SPORTIF results."
Heartbeat – Sept 2003
Weber
ESC 2003
ESTEEM: Fuster summary
Our laboratory has been involved since
the beginnings of antithrombin
"[These are] new types of drugs, which
certainly are going to be very
successful in the future."
Critical issues for the future:
• Effect on liver
• Cost
Heartbeat – Sept 2003
Fuster
ESC 2003
CHARM: Trials
Candesartan in Heart Failure: Assessment of
Reduction in Mortality and Morbidity
7601-patient trial divided into smaller studies of
three populations:
• Patients with LV dysfunction intolerant to ACE
inhibitors (the CHARM-Alternative trial)
• Patients with LV dysfunction already taking ACE
inhibitors (the CHARM-Added trial)
• Patients with preserved LV function (the CHARMPreserved trial)
Heartbeat – Sept 2003
ESC 2003
CHARM-Overall: Results
Placebo
Candesartan
35
Events (%)
30
25
20
15
10
5
0
CV death
CHF
Combined
Lancet 2003; 362: 759–66
Heartbeat – Sept 2003
ESC 2003
CHARM-Alternative: Results
Placebo
Candesartan
40
Events (%)
35
30
25
20
15
10
5
0
CV death
CHF
Combined
Lancet 2003; 362: 772–76
Heartbeat – Sept 2003
ESC 2003
CHARM-Added: Results
Placebo
Candesartan
45
Events (%)
40
35
30
25
20
15
10
5
0
CV death
CHF
Combined
Lancet 2003; 362: 767–71
Heartbeat – Sept 2003
ESC 2003
CHARM-Preserved: Results
Placebo
Candesartan
Events (%)
25
20
15
10
5
0
CV death
CHF
Combined
Lancet 2003; 362: 777–81
Heartbeat – Sept 2003
ESC 2003
CHARM: Is candesartan the answer?
We still think for LV dysfunction, ACE
inhibitors were the drug of choice
• But in patients who cannot tolerate
ACE inhibitors, is candesartan the
answer?
Heartbeat – Sept 2003
Fuster
ESC 2003
CHARM: Support for ARBs
Effective inhibition of the angiotensinrenin system is mandatory in patients
with heart failure and coronary
disease
"This really boosts enormously the
evidence base on the efficacy side for
the ARBs."
Heartbeat – Sept 2003
Cannon
ESC 2003
CHARM: Val-HeFT results
Placebo
Valsartan
35
Events (%)
30
25
20
15
10
5
0
Mortality and morbidity Hospitalization for CHF
N Engl J Med 2001;345:1667-75
Heartbeat – Sept 2003
ESC 2003
CHARM: ARB popularity
The high tolerability of ARBs may make
them very popular even if a patient
hasn't exhausted the possibility of ACE
inhibitors
In CHARM-Added, is the effect of the
combination any different from simply
upping the dose of the ACE inhibitor?
Heartbeat – Sept 2003
Weber
ESC 2003
CHARM: Physiology
CHARM confirms ARBs as an alternative to
ACE-inhibitors
The physiological axis here is the reninangiotensin-aldosterone axis, and the
aldosterone receptor antagonists will
also have effects
"ACE inhibitors alone are not
necessarily enough."
Heartbeat – Sept 2003
Ferguson
ESC 2003
CHARM: Side effects
Cough was major reason for intolerance
to ACE inhibitor
ARB blockers had minimal side effects
What will the side effects be of two drugs
both working in the ACE pathway?
"It's very striking data but I'm not
sure how applicable it is going
to be in the real world."
Heartbeat – Sept 2003
Fuster
ESC 2003
CHARM: Compliance
Difficult to persuade patients to stay on
six or eight drugs for their heart
failure
Patients are so worried about their
symptoms and possible hospitalization
that most are very motivated
The ARBs do seem to not add to the sideeffect burden
Heartbeat – Sept 2003
Weber
ESC 2003
CHARM: New-onset diabetes
Placebo
Candesartan
8
Events (%)
7
6
5
4
3
2
1
0
Diabetes
Hypotension
Hyperkalemia
Lancet 2003; 362: 759–66
Heartbeat – Sept 2003
ESC 2003
CHARM-Preserved: Major results
End point
Candesartan
(n=1514)
Placebo
(n=1509)
Adjusted HR
(95% CI)
p
CV death/CHF
hospitalization
22.0%
24.3%
0.86
(0.74-1.00)
0.051
CV death
11.2%
11.3%
0.95
(0.76-1.18)
0.635
CHF
hospitalization
15.9%
18.3%
0.84
(0.70-1.00)
0.047
Lancet 2003; 362: 777–81
Heartbeat – Sept 2003
ESC 2003
CHARM-Preserved: Very promising
This is an effect in a population where we
have nothing that works right now
This was the lowest-risk group of the
CHARM trial, so a larger trial would be
needed
"I think we can really look forward
to that as finally a therapy that
will be helpful for this group."
Heartbeat – Sept 2003
Cannon
ESC 2003
CHARM-Preserved: Age
Average age in CHARM-Preserved was 67
This type of heart failure is usually found
in the elderly, age >70
We don't have much guidance outside of
diuretic therapy, so why not use an
ARB?
14-15% reduction of hospitalization
is very worthwhile in HF
Heartbeat – Sept 2003
Weber
ESC 2003
CHARM: Enthusiasm
Excitement seems based on two issues:
• Adding an ARB to the conventional ACE
inhibitor
• A hope for patients with preserved LV
function
Heartbeat – Sept 2003
Fuster
ESC 2003
CHARM: Ferguson summary
Moderate-plus level excitement
No huge surprises in the overall trial
CHARM-Preserved sets the stage for the
future
"It was not earth-shattering, but I think
it's very, very encouraging."
Heartbeat – Sept 2003
Ferguson
ESC 2003
CHARM: Weber summary
CHARM suggests the Val-HeFT finding
that adding an ARB on top of an ACE
inhibitor wasn't effective if a beta
blocker was in place was an aberrant
finding
"That to me is very helpful because I had
a lot of trouble explaining why the
three drugs didn't work so well
together; now I don't have to
worry about it anymore."
Heartbeat – Sept 2003
Weber
ESC 2003
CHARM: Cannon summary
It provides stronger evidence to reinforce
things we already knew
"This is for real and we need to really try
to implement effective inhibition of
the angiotensin, renin, and
aldosterone axis."
Heartbeat – Sept 2003
Cannon
ESC 2003
EUROPA
Adding perindopril to standard therapy in patients
with stable CAD
• 12 218 patients
• Randomized to perindopril (8 mg once daily) or
placebo
• Primary end point: CV death, MI, and cardiac
arrest
• Four-year follow-up
Heartbeat – Sept 2003
ESC 2003
EUROPA: Results
Events (%)
Placebo
10
9
8
7
6
5
4
3
2
1
0
Primary end
point
Perindopril
Nonfatal MI
CHF
Lancet 2003; 362: 782–88
Heartbeat – Sept 2003
ESC 2003
EUROPA: HOPE results
Events (%)
Placebo
18
16
14
12
10
8
6
4
2
0
Combined
end point
Perindopril
CV death
MI
Stroke
ESC 1999
Heartbeat – Sept 2003
ESC 2003
EUROPA: Broader population
Very powerful data
EUROPA suggests ACE-inhibitor benefit
may extend out broadly into an at-risk
population
"I knew that ACE inhibitors were good, but
I had no idea how good they are in a
broader population of patients."
Heartbeat – Sept 2003
Ferguson
ESC 2003
EUROPA: Stroke results
Events (%)
Placebo
5
5
4
4
3
3
2
2
1
1
0
Heartbeat – Sept 2003
HOPE
ACE inhibitor
EUROPA
ESC 2003
EUROPA: Signal to noise
The lack of stroke effect may have to do
with EUROPA using lower-risk patients
"We may be losing the signal in the noise
for right now. Two hundred strokes in
the overall population is not a lot to be
able to try to tease out an effect."
Heartbeat – Sept 2003
Ferguson
ESC 2003
EUROPA: Blood pressure
Possible explanation of the difference
between EUROPA and HOPE:
• Lack of power
• Blood pressure
There was a smaller change in blood pressure
in EUROPA than there was in HOPE
Heartbeat – Sept 2003
Fuster
ESC 2003
EUROPA: Class effect?
Salim Yusuf: Does this show anything
different from what we saw with ramipril
in HOPE?
EUROPA investigators: Fantastic results in a
very low-risk population that is different
from HOPE
Sidney Smith: This is adding to the
HOPE study
Heartbeat – Sept 2003
Fuster
ESC 2003
EUROPA: Stronger evidence
Cardiologists are always skeptical of new
things
Guidelines did not adopt full HOPE
population for treatment with ACE
inhibitors when it came out
"There was some reluctance to say, 'put
this in the drinking water for
coronary disease.' I think that
can now go away."
Heartbeat – Sept 2003
Cannon
ESC 2003
EUROPA: Class effect
"It is pretty clear this is a class effect."
ACE-inhibitor story started with captopril
in the SAVE trial and then continued in
the SOLVD study
Effect has been seen with captopril,
ramipril, and perindopril
All CAD patients should be on an
ACE inhibitor
Heartbeat – Sept 2003
Cannon
ESC 2003
EUROPA: Building on previous data
EUROPA builds on the HOPE trial
• Gives us a new ACE inhibitor
• Extends the population
Not a huge advance but it expands our
horizons
"ACE inhibitors, while not added to
the drinking water, maybe ought
to be put in the saltshakers."
Heartbeat – Sept 2003
Ferguson
ESC 2003
EUROPA: Clarifying data
EUROPA is confirmatory rather than
breakthrough
Removes the argument that HOPE was a
hypertension trial rather than a highrisk cardiovascular trial
"It's confirmatory but very important
confirmatory, and I'm delighted
it turned out this way."
Heartbeat – Sept 2003
Weber
ESC 2003
Summary: Topics
ESTEEM
Adds the arterial system as an
option for ximelagatran
CHARM
ARB as an alternative or in
addition to ACE inhibitor for CHF
patients
EUROPA
All patients with CAD should be
treated with an ACE inhibitor
Heartbeat – Sept 2003
ESC 2003
Final word: The right track
These studies show we are on the right track
• Antithrombotic therapy in coronary
disease
• Treating cardiac failure with the ACE
pathway
• ACE inhibition for CAD patients
regardless of risk
Heartbeat – Sept 2003
Fuster
ESC 2003
Final word: Cannon
The inhibition of the renin-angiotensinaldosterone system is extremely
important
"I think that has become now a
mandatory component of heart failure
and coronary disease management."
Heartbeat – Sept 2003
Cannon
ESC 2003
Final word: Ferguson
Older forms of therapy can be used in
broader populations (ACE inhibitors in
at-risk CAD patients)
Newer forms of therapies can extend what
we can do (ARBs can add to or
substitute for ACE inhibitors)
New compounds on the horizon that
may supplant older forms of
therapy (oral antithrombins can
replace warfarin)
Heartbeat – Sept 2003
Ferguson
ESC 2003
Final word: Weber
Confidence: These studies confirm what
we predicted
"Had the results not turned out the way
they had, I think we would have been
devastated."
These results should give cardiologists
confidence they are on the right
track
Heartbeat – Sept 2003
Weber
ESC 2003
Next session
GRACIA-2
Immediate thrombolysis plus PCI
Aspirin resistance
Present in many patients
DECOPI
Late-artery opening
BASEL
BNP testing and diagnosing heart
failure
Heartbeat – Sept 2003