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ESC 2002
ESC 2002
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 – Sep 2002
Brooklyn, NY
ESC 2002
Topics
Acute coronary syndromes
MAGIC
OPTIMAAL
RITA-3
BNP prognostics
Off-pump surgery
Stem cells
Heartbeat – Sep 2002
ESC 2002
MAGIC: Trial design
MAGnesium In Coronaries (MAGIC)
PI: Elliot Antman
• 6213 MI patients.
• Randomized to IV magnesium or placebo.
• Primary end point: all-cause mortality at
30 days.
Heartbeat – Sep 2002
ESC 2002
MAGIC: Mortality results
20%
No difference in 30-day mortality
between magnesium and
placebo.
18%
16%
14%
12%
No significant differences in any
subgroup.
10%
8%
No benefit or harm seen in
secondary outcomes.
6%
4%
2%
0%
Death
“Magnesium is dead in the water.”
Rory Collins
Mg
Heartbeat – Sep 2002
Placebo
ESC 2002
MAGIC: Time to move on
There were intriguing questions generated by
earlier trials.
“But when you put it to the test, it doesn’t
make any difference. So, let’s move on.”
Ferguson
Heartbeat – Sep 2002
ESC 2002
MAGIC: Rationale for the trial
LIMIT-2: Mg started before thrombolysis.
ISIS 4: Mg started several hours after
thrombolysis.
The negative results in ISIS-4 could have
been due to the delay.
MAGIC went back to early administration
of Mg.
Cannon
Heartbeat – Sep 2002
ESC 2002
MAGIC: A might-have-been?
Did magnesium never have a chance
because ACE inhibitors and thrombolysis
got there first?
“We really don’t have any information
that would allow us to make that
judgment.”
Weber
Heartbeat – Sep 2002
ESC 2002
OPTIMAAL: Trial design
Optimal Trial in Myocardial Infarction
with the Angiotensin II Antagonist
Losartan (OPTIMAAL)
PI: Kenneth Dickstein
• 5477 patients.
• Acute MI.
• Losartan 50 mg once daily vs captopril
50 mg 3 times daily mm Hg.
• Primary end point: all-cause mortality
at 2.7 years follow-up.
Heartbeat – Sep 2002
ESC 2002
OPTIMAAL: Results
Rate of endpoint
captopril
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
Heartbeat – Sep 2002
p=0.069
Mortality
losartan
p=0.032
CV death
Lancet 360:752-760
ESC 2002
OPTIMAAL: ACE vs ARB
The angiotensin axis is important, but ACE
inhibitors are still superior to ARBs in the
doses we’ve tested.
New tools help, but losartan is still just a
good alternative therapy.
There is interest in higher doses of losartan.
Heartbeat – Sep 2002
Ferguson
ESC 2002
OPTIMAAL: A Greek tragedy
The results were known well over a year
ago.
ELITE-2 also had a trend favoring
captopril with the same doses.
VAL-HeFT used a genuine dose (160 mg
twice a day) of valsartan and got FDA
approval for heart failure.
50 mg is a nonsense dose.
Heartbeat – Sep 2002
Weber
ESC 2002
OPTIMAAL: Misnamed
The name is ironic because OPTIMAAL
tested suboptimal levels of losartan.
Dose is critical–-we haven’t tested proper
doses of losartan yet.
“The whole rationale in this field is moving
toward complete blockade of this axis,
so to use a very low dose goes counter
to the thinking of how this pathway can
be best inhibited and outcomes
improved.”
Heartbeat – Sep 2002
Cannon
ESC 2002
OPTIMAAL: Appropriate dosing
Losartan as a replacement for captopril
should use a minimum of 100 mg.
We should push the doses as high as one
appropriately can because that goes
after the pathophysiology of the
problem.
Cannon
Heartbeat – Sep 2002
ESC 2002
OPTIMAAL: ARBs
Losartan should be used at 50 mg bid.
LIFE titrated patients from 50 mg a day to
as much as 100 mg daily.
The advantage in LIFE was a stroke
advantage, not an MI advantage.
“For all the excitement with the ARBs
they’ve still got to prove themselves
as having a cardioprotective effect.”
Heartbeat – Sep 2002
Weber
ESC 2002
RITA-3: Trial design
Randomized Intervention Trial of
unstable Angina (RITA-3)
PI: Keith AA Fox
• 1810 patients with non-ST-elevation Ml
or unstable angina.
• Randomized to conservative or
interventional approach.
• Primary end points: death, MI, and
refractory angina at 4 months and
death and MI at 1 year.
Heartbeat – Sep 2002
ESC 2002
RITA-3: Defining risk
Troponin is the most potent: high vs low risk
(FRISC II).
ST-segment changes on the EKG also gives
high vs low risk.
TIMI risk score ranges from 0 to 7, defining
low-, intermediate-, and high-risk groups.
TACTICS-TIMI 18 and FRISC II both found
intermediate to high risk benefited
from an early intervention strategy.
Heartbeat – Sep 2002
Cannon
ESC 2002
RITA-3: Heart failure as a risk factor
Admission with heart failure is a very
important predictor of death but a less
important predictor of recurrent MI or
recurrent ischemia.
Markers of the burden of disease are more
effective for predicting the broader impact
of a therapy.
Cannon
Heartbeat – Sep 2002
ESC 2002
RITA-3: Moderate risk?
Patients in RITA-3 are called moderate risk
but:
• 75% of the patients were troponin
positive.
• Exclusion criteria included 2x normal CK
elevation.
• The CK-negative/troponin-positive
group is at highest risk of recurrent
ischemic events.
Heartbeat – Sep 2002
ESC 2002
RITA-3: Event rate
Interventional
Rate of endpoint
16%
14%
12%
10%
p=0.001
14.5
Conservative
p=0.58
9.6
7.6
8%
8.3
6%
4%
2%
0%
Heartbeat – Sep 2002
4 months
1 year
ESC 2002
ESC 2002
RITA-3: Trial comparison
Interventional
Conservative
Death or MI in 1 year
25%
20%
15%
10%
5%
0%
VANQWISH
Heartbeat – Sep 2002
T-T 18
FRISC II
RITA-3
ESC 2002
ESC 2002
RITA-3: More cath labs
RITA-3 and TACTICS-TIMI used an early
invasive approach, FRISC II a little later.
“The hope is that this will really spur Canada
and the European countries to start
building some more cath labs and start
talking with their health authorities to say
this is way we can improve outcomes for a
large group of patients.”
Heartbeat – Sep 2002
Cannon
ESC 2002
RITA-3: So many patients
We should see cath rates in the 80% to 85%
range if we follow evidence-based
medicine:
• Between 2/3 and 3/4 UA/NSTEMI
patients are moderate to high risk.
• Three million estimated UA/NSTEMI
patients in Europe and the US.
• Even in clinical trials, half the
conservative therapy group goes on to
cath eventually.
Heartbeat – Sep 2002
Cannon
ESC 2002
RITA-3: Angina
Individual endpoint
at 1 year
Interventional
Conservative
120
100
80
60
40
20
0
Heartbeat – Sep 2002
Death
MI
Refractory
angina
Lancet 360:743-751
ESC 2002
RITA-3: MI using standard
definition
Interventional
Conservative
Death
MI
Death or MI at 1 yr
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
Heartbeat – Sep 2002
Death or MI
Lancet 360:743-751
ESC 2002
RITA-3: Inadequate resources
“Even in this country we do have a great
inadequacy of resources.”
Most of the hospitals in Brooklyn do not have
the resources to get quickly to a cath lab
and to provide the appropriate
intervention.
“This is a big problem over here as well.”
Heartbeat – Sep 2002
Weber
ESC 2002
RITA-3: Summary
RITA-3 adds to the thinking that acute
coronary syndromes fall more and more
into the interventional arena.
What will the economics of this mean to
poorer countries?
Fuster
Heartbeat – Sep 2002
ESC 2002
BNP prognostics: Trial design
BNP as a prognostic for sudden death in HF
PI: Rudolf Berger
• 452 ambulatory patients with LVEF ≤
35%.
• Primary end point: sudden death over 3
years.
Heartbeat – Sep 2002
ESC 2002
BNP: Mortality results
<2.11
2.11+
20%
18%
16%
A log BNP ≥ 2.11 was the only
independent predictor of
sudden death
14%
12%
10%
8%
This could discriminate who is a
candidate for an ICD
6%
4%
2%
0%
Death
Heartbeat – Sep 2002
ESC 2002
BNP: Prognostic tool
The study is fascinating because this takes
BNP from a diagnostic to a prognostic
tool.
Maybe we have to start monitoring BNP in
our heart failure patients.
Patients with so-called mild heart failure
may be the people for whom this test
would be particularly helpful.
Heartbeat – Sep 2002
Weber
ESC 2002
BNP: Screening patients
With a 20% total mortality rate, it’s hard to
say how “mild” the heart failure really is.
The predictive nature of BNP is really
intriguing because we are all looking for
ways to stratify patients for ICD.
“I’d like to see this extended and confirmed.”
Heartbeat – Sep 2002
Ferguson
ESC 2002
BNP: Questions about ICDs
Patients with MI and low EF should receive
ICDs, but we are still looking at ways to
screen the patients who will most benefit.
For cardiac failure not related to coronary
artery disease, do we know if ICDs are
even useful?
Fuster
Heartbeat – Sep 2002
ESC 2002
BNP: We need risk stratification
We need tools to pick out the patients who
would most benefit from ICDs, because
the costs could be prohibitive.
Risk stratification is the right strategy, as it
was with ACS.
I’m hoping BNP can be measured in MADIT II
and in upcoming trials.
Heartbeat – Sep 2002
Cannon
ESC 2002
BNP: Two patients
Myocardial infarction
EF = 35%
Dilated cardiomyopathy
EF = 35%
Heartbeat – Sep 2002
ESC 2002
BNP: Two patients
Monitor the cardiomyopathy patient,
maybe measure BNP levels, look for an
indication to use an ICD.
I don’t think this particular information
really speaks to patients with AMI. It’s
not clear what the proper approach
should be.
Heartbeat – Sep 2002
Weber
ESC 2002
BNP: AMI
BNP will rise in the first 8 to 12 hours to a
peak and then gradually descend with
treatment.
Maybe we need to treat patients
differently, depending on how recent
their MI.
“[BNP] is now the new CRP for heart
failure and I think we’ll have much
more information in the next 6 to 12
months.”
Heartbeat – Sep 2002
Cannon
ESC 2002
BNP: Physiology matters
“It brings us back to the issue that
physiology matters.”
The metabolic pathways underlying this
process is important.
“We just don’t quite understand enough
about it to figure out exactly what’s going
on yet.”
Heartbeat – Sep 2002
Ferguson
ESC 2002
Off-pump CABG: Trial design
Patency of Off-Pump CABG
PI: Brompton group
• 103 patients.
• 54 off-pump, 49 conventional CABG.
• Primary end point: graft patency at 3months.
Heartbeat – Sep 2002
ESC 2002
Off-pump CABG: Patency results
Off-pump
On-pump
100%
Not a significant finding
80%
If the grafts are more occluded,
are all the advantages of offpump surgery irrelevant?
60%
40%
Do we need to look deeper into
what is happening with offpump CABG?
20%
0%
Heartbeat – Sep 2002
Patancy
Fuster
ESC 2002
Off-pump CABG: Suboptimal patency
The most important thing is graft patency.
“If it were me or my family member, I’d
definitely go for the real thing.”
“I suppose it’s a replay of the PCI story,
that suboptimal stent deployment leads
to suboptimal results.”
Cannon
Heartbeat – Sep 2002
ESC 2002
Off-pump CABG:
Tweaking the technique
We improved adjunctive therapy with PCI
over time, we can do the same here.
“I think that off-pump is here to stay. I think
we may just need to tweak it and may
need to do the larger-scale trials looking
closely at patency but also making an
effort to optimize the adjunctive
therapy.”
Heartbeat – Sep 2002
Ferguson
ESC 2002
Off-pump CABG: Experience
Two or 3 patients made all the difference
in this trial.
These results must be very dependent on
the skill and experience of the
surgeons. We might see no difference
between off-pump and on-pump
patency in 5 or 6 years
“But I suspect that in a handful of years
we’re going to see much more shift to
the off-pump method.”
Heartbeat – Sep 2002
Weber
ESC 2002
Stem cells: Mode of delivery
SYLVAIN’s PIC
Heartbeat – Sep 2002
ESC 2002
Stem cells: Ventricular function
Before
cell therapy
3-month
follow-up
p
30+13
12+7
0.005
Infarct region as perfusion 174+99
defect (cm2)
128+71
0.016
Stroke volume index
(mL/m2)
49+7
56+7
0.010
Infarction wall movement
velocity (mm/s)
2.0+1.1
4.0+2.6
0.028
Function parameter
Infarct region as
functional defect* (%)
*Percentage of hypokinetic, akinetic, or dyskinetic regions
Heartbeat – Sep 2002
Strauer BE et al. Circulation 2002
ESC 2002
Stem cells: New cardiomyocytes
Stromal-mesenchymal
pathway
Bone marrow
Pluripotent cells
Skeletal muscle,
cardiomyocytes
Heartbeat – Sep 2002
ESC 2002
Stem cells: Arrhythmia
There are concerns about increased risk of
arrhythmias with this technique.
We need studies with more patients.
“As we look at heart failure, as we look at
acute myocardial infarction, I think [stem
cell therapy] is an area that we’re going
to be seeing an awful lot more from. ”
Heartbeat – Sep 2002
Ferguson
ESC 2002
Stem cells: A new hope
“The whole field of acute MI has revolved
around the need for early salvage
because you can’t get the heart cells
back. But if in fact you can repair the
heart then it’s just a wonderful new
hope.”
Cannon
Heartbeat – Sep 2002
ESC 2002
Summary: MAGIC
Randomized MI patients to IV magnesium or
placebo.
Absolutely no effect on mortality at 30 days.
“We have to forget about magnesium, at
least for the next 25 years.”
Fuster
Heartbeat – Sep 2002
ESC 2002
Summary: OPTIMAAL
Losartan 50 mg once daily vs captopril 50 mg
3 times daily.
Trend favored captopril, but questions remain
because the dose of losartan was so low.
“The issue is not closed.”
Fuster
Heartbeat – Sep 2002
ESC 2002
Summary: RITA-3
NSTEMI/UA patients randomized to
conservative or interventional approach.
Intervention is much better than
conservative therapy.
“This really moves the field of acute coronary
syndromes more and more toward the
interventional area.”
Heartbeat – Sep 2002
Fuster
ESC 2002
Summary: BNP
BNP was a predictor of sudden death in
patients with chronic cardiac failure.
This opens the possibility of screening
patients for ICD use.
The data don’t translate into AMI patients,
where BNP levels are highly variable.
Heartbeat – Sep 2002
Fuster
ESC 2002
Summary: Off-pump surgery
We all think off-pump surgery lets patients
go home early and has fewer bleeding
complications.
Graft patency was better in the on-pump
CABG patients.
We need to follow this new technology
closely.
Heartbeat – Sep 2002
Fuster
ESC 2002
Summary: Stem cells
Injection of pluripotent bone-marrow cells
into myocardium post-MI.
No inflammatory response, potential
improvement in ventricular function, but a
possible increase in arrhythmia.
Heartbeat – Sep 2002
Fuster
ESC 2002
Final word: SOLVD
Patients in the original SOLVD trial got 8
to 9 months of increased life
expectancy from aggressive ACE
inhibitor treatment.
It just emphasizes how the newer
modalities we talked about today may
be the ones that will make a real
difference for people with heart
failure.
Heartbeat – Sep 2002
Weber
ESC 2002
Final word: Interventional strategy
In the ACS arena, the invasive strategy has
held up as the best management
strategy.
“Hopefully we’ll start to see a move toward
more patients being referred
appropriately for cardiac catheterization
and probably a need for more cath
labs.”
Heartbeat – Sep 2002
Cannon
ESC 2002
Final word: Dose
“The dose of a given drug is almost as
important as the drug itself.”
We need to make sure we are dosing
appropriately in our practice. It’s not
just enough to be on the right drug, the
dose must be the right dose.
Heartbeat – Sep 2002
Cannon
ESC 2002
Final word: 3 lessons
1: We need clinical trials:
more and more important at meetings.
2: If you do trials, you need to do them right:
dosing, logistics, understand the biology.
3: Care moves forward: We have a
responsibility to take the information and
apply it to real-world practice.
Heartbeat – Sep 2002
Ferguson
ESC 2002
ESC 2002: End
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 – Sep 2002
Brooklyn, NY