Transcript ACC 2004 - Medscape

ACC 2004
ACC 2004: New pathways in ACS
and heart failure management
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Christopher Cannon MD
Associate Professor of Medicine
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 – March 2004
Brooklyn, NY
ACC 2004
Topics
PROVE-IT
Atorvastatin 80 mg vs
pravastatin 40 mg in ACS
SYNERGY
Enoxaparin vs unfractionated heparin
in ACS
SCD-HeFT
ICD use in patients with heart failure
and LV dysfunction
Heartbeat – March 2004
ACC 2004
Pravastatin or Atorvastatin
Evaluation and Infection
Therapy
PROVE-IT
Heartbeat – March 2004
ACC 2004
PROVE-IT: Design
Intensive and moderate lipid lowering with statin
therapy after acute coronary syndrome (ACS)
(N Engl J Med 2004; 350: published March 8, 2004)
• 4162 patients with ACS (<10 days)
• Pravastatin (40 mg daily) vs atorvastatin (80 mg
daily)
• Primary end point: a composite of all-cause
mortality, MI, unstable angina requiring
hospitalization, revascularization, and stroke
• Two-year follow-up
Heartbeat – March 2004
ACC 2004
PROVE-IT: LDL reduction
LDL
cholesterol
Pravastatin Atorvastatin
40 mg
80 mg
(n=1973)
(n=2003)
Final LDL
cholesterol
(mg/dL)
95.0
Heartbeat – March 2004
62.0
N Engl J Med 2004; 350
ACC 2004
PROVE-IT: Results
Pravastatin Atorvastatin
40 mg
80 mg
p
(n=1973)
(n=2003)
Primary
composite
end point 26.3
(%)
22.4
0.005
16% reduction in risk favoring atorvastatin
Heartbeat – March 2004
N Engl J Med 2004; 350
ACC 2004
PROVE-IT: Lower is better
"The change in cholesterol really parallels
the change in clinical events."
• LDL cholesterol as a major target to
prevent major cardiovascular events
and death
Heartbeat – March 2004
Cannon
ACC 2004
PROVE-IT: Entry criteria
PROVE-IT provides new data to support
the use of statins in ST-elevation MI
• Extends benefit of statins across
ACS spectrum
"To me, that's very impressive
because it really tells us we're
dealing with some sort of
fundamental mechanism."
Heartbeat – March 2004
Weber
ACC 2004
PROVE-IT: Components of end point
The individual cardiac end points
benefited from more intensive lipidlowering therapy.
"It is really a striking feature of the trial
in how strongly the events do line up
in favor of the higher-dose intensive
therapy."
Heartbeat – March 2004
Ferguson
ACC 2004
PROVE-IT: Baseline LDL levels
Patients with a baseline LDL
cholesterol >125 mg/dL appear to
benefit most
• Lower baseline LDL cholesterol and
patients already taking a statin do
not benefit as much
Heartbeat – March 2004
Ferguson
ACC 2004
PROVE-IT: 30 days
Curves begin to diverge at 30 days
• Curves similar in terms of the
overall time course
• Further study is needed to assess
whether "it takes more time" for
benefit to occur in patients with
lower baseline LDL
Heartbeat – March 2004
Cannon
ACC 2004
PROVE-IT: Benefit timing
Is the benefit of atorvastatin obtained
early on or do the curves continue to
separate after nine months?
Heartbeat – March 2004
Fuster
ACC 2004
PROVE-IT: Tough questions
"Is the glass half full or is it half empty?"
• Most benefit achieved at nine
months
• Curves may continue to diverge at a
rate commensurate with other longterm studies
Heartbeat – March 2004
Ferguson
ACC 2004
PROVE-IT: Is it LDL or the drug?
Impressive results, but clinicians now
must decide whether results are
attributable to LDL lowering, the drug,
the setting, or other factors
"Study reinforces the importance of LDL
lowering, but I'm not sure LDL is
everything here."
Heartbeat – March 2004
Ferguson
ACC 2004
PROVE-IT: Pleiotropic effects
"Can we get the same beneficial endpoint results as long as we get the
same reduction in LDL?"
• Would a combination of ezetimibe
and a statin be as effective as a
high dose of atorvastatin?
"I'm pretty willing to accept the
idea that it's the LDL."
Heartbeat – March 2004
Weber
ACC 2004
PROVE-IT: What about REVERSAL?
REVERSAL
LDL-cholesterol reduction alone did not
explain the differences in efficacy
between the two statins
Progression rate at any level of LDL
cholesterol reduction was lower with
atorvastatin compared with
pravastatin
Heartbeat – March 2004
JAMA 2004;291:1071-1080
ACC 2004
PROVE-IT: Revascularization
More than two thirds of patients
underwent PCI
• Consistent message about the benefit
of statins in percutaneously
revascularized ACS patients
Heartbeat – March 2004
ACC 2004
PROVE-IT: Case study 1
How would you treat a patient with
chronic coronary artery disease and
LDL-cholesterol level of 110 mg/dL
taking pravastatin 40 mg daily?
• Pravastatin 80 mg?
• Atorvastatin 80 mg?
• Add ezetimibe?
Heartbeat – March 2004
Fuster
ACC 2004
PROVE-IT: Case study 1
In stable patients, follow guidelines to get
LDL cholesterol under 100 mg/dL
• Pravastatin 80 mg may bring the
patient under 100 mg/dL
• Ezetimibe may also provide "boost"
to bring LDL down another 10% to
15%
Heartbeat – March 2004
Cannon
ACC 2004
PROVE-IT: Case study 2
Would you make any changes to
therapy in a patient with chronic
coronary artery disease and LDL
cholesterol level of 89 mg/dL taking
pravastatin 40 mg daily?
Heartbeat – March 2004
Fuster
ACC 2004
PROVE-IT: Case study 2
"There is no evidence at this point that
driving down LDL any further will
make any meaningful difference."
• Still, hard to ignore PROVE-IT even
without evidence in more stable
patients
• May start patients on more powerful
doses
Heartbeat – March 2004
Weber
ACC 2004
PROVE-IT: Is it the drug or the LDL?
What therapy would you start with to
achieve LDL cholesterol 60 to 70
mg/dL in a patient with ACS?
Heartbeat – March 2004
ACC 2004
PROVE-IT: Is it the drug or the LDL?
"Trying to answer the question of is it
the drug or is it the LDL, at least
based on all the measures of CRP, it
looks like this tracks with the LDL and
not the drug or the type of drug."
Heartbeat – March 2004
Cannon
ACC 2004
PROVE-IT: How low to go?
In a patient with chronic coronary artery
disease, as a clinician, are you satisfied
with a LDL cholesterol level of 95 mg/dL?
Heartbeat – March 2004
ACC 2004
PROVE-IT: How low to go?
Not thrilled with getting LDL cholesterol
down to just 95 mg/dL.
"It seems ridiculous to say that because
only a few short months ago, I
thought getting down to 100 mg/dL
was pretty adventurous."
Heartbeat – March 2004
Weber
ACC 2004
PROVE-IT: How low to go?
"I'm happy with 95 mg/dL in a stable
patient."
• Run into danger of simply "chasing
numbers"
Heartbeat – March 2004
Ferguson
ACC 2004
PROVE-IT: Summary
In ACS patients, aim to lower LDL levels
to 60 or 70 mg/dL as shown in PROVEIT
In chronic disease, aim to lower LDL
cholesterol levels below 100 mg/dL
• No evidence to support using
aggressive therapy to bring LDL
levels to 60 or 70 mg/dL in stable
patients
Heartbeat – March 2004
ACC 2004
Superior Yield of the New
Strategy of Enoxaparin,
Revascularization, and
Glycoprotein IIb/IIIa
Inhibitors
SYNERGY
Heartbeat – March 2004
ACC 2004
Enoxaparin in past studies
ESSENCE, TIMI 11b
• Enoxaparin appeared hopeful in
terms of easy use, little bleeding
• Many patients did not undergo
intervention or receive IIb/IIIa
inhibitors
SYNERGY
• High-risk population with non-STsegment elevation MI
Heartbeat – March 2004
ACC 2004
SYNERGY: Design
• 10 000 high-risk ACS patients in 467
centers, with positive CK MB or troponin
and ST elevation or depression
• Aged 60 years or older
• Enoxaparin vs unfractionated heparin
• Most patients underwent interventions
and received glycoprotein IIb/IIIa
inhibitors
• Primary end point of death/MI at 30 days
Heartbeat – March 2004
ACC 2004
SYNERGY: Results
16
Enoxaparin
14
Unfractionated heparin
14.5
End points (%)
14
12.7
11.7
12
10
8
6
4
3.2
3.1
2
0
Death/MI
Heartbeat – March 2004
Death
MI
ACC 2004
ACC 2004
SYNERGY: Analogy to PROVE-IT
"The results turned out to be a little
different from what we thought going
into the trial."
PROVE-IT
Noninferiority trial that showed
superiority
SYNERGY
Superiority trial that showed
noninferiority
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Background
Were low-molecular-weight heparins safe
in a rapidly, early-invasively managed
population, because you are bringing
them forward blindly?
"From an efficacy standpoint they are at
least as good."
Ferguson
Heartbeat – March 2004
ACC 2004
SYNERGY: The bleeding issue
Multiple scales and ways to look at
bleeding
"Anybody that has used enoxaparin in
these circumstances wouldn't argue
that there probably is a little bit more
bleeding, but is it enough that there
should be a problem?"
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Bleeding
Bleeding
Enoxaparin
(%)
UFH
(%)
p
GUSTO severe
bleeding
2.9
2.4
0.107
H&H drop/ICH
15.2
12.5
0.001
TIMI major
bleeding
9.1
7.6
0.008
Transfusions
17.0
16.0
0.155
H&H=hemoglobin and hematocrit; ICH=intracranial hemorrhage
Heartbeat – March 2004
ACC 2004
ACC 2004
SYNERGY: Findings
• Most bleeding in patients
undergoing bypass surgery (20% of
the study population)
• Very invasive management strategy
(25% in the cath lab six hours after
randomization)
"Enoxaparin showed efficacy that was at
least as good as [heparin] and
numerically more bleeding…,but not of
an order that we thought was a
clinical problem."
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Duration of treatment
How do you react to the critics that argue
low-molecular-weight heparin may not
be necessary; even the cost of
unfractionated heparin is lower?
The time patients were treated may have
been a factor
"You need to give a
drug for it to have
a benefit."
Heartbeat – March 2004
Cannon
ACC 2004
SYNERGY: Time to cath lab
ESSENCE, TIMI IIb
Benefits of enoxaparin
INTERACT
"Dramatic clinical benefits"; patients
went to the cath lab after four days
A to Z
Shortest time to cath lab and exposure
to drug; trend to better outcome with
11% improvement with enoxaparin
Heartbeat – March 2004
ACC 2004
SYNERGY: Clinical practice
In my practice:
• With more than 24 hours to the cath
lab I use enoxaparin, because
events will be reduced by 15% to
20%
• Within hours to cath lab I would use
unfractionated heparin
• Switching from one agent to
the other in the cath lab
causes problems
Heartbeat – March 2004
Cannon
ACC 2004
SYNERGY: Dilemma
Reminds me of the comparison between
ximelagatran and Coumadin in
SPORTIF-V
• Looking for the drug that is more
simple and even slightly more
effective
Creates a dilemma, because you
don't exactly know which
patient is going to the
cath lab
Heartbeat – March 2004
Weber
ACC 2004
SYNERGY: Trends
"We saw some intriguing trends relating
to the duration of therapy, the time
from randomization to time of
intervention, that suggested that
longer durations of therapy gave more
of an opportunity for the drug to be
more effective."
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Enoxaparin
• Patients randomized to enoxaparin
were supposed to continue this drug
forward into the lab
• Some physicians switched patients
back over to UFH in the lab
• This increased the risk for bleeding
"If there is going to be a longer delay of
therapy, the evidence favors
enoxaparin."
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Crossover
One of the issues of this study: use of
enoxaparin in patients going to the
cath lab
• Many patients were either crossing
over to or had been started on
another drug
How was the bleeding in "clean" patients,
who were on no drug going into the
study and continued on the same
study drug into the cath lab?
Heartbeat – March 2004
Cannon
ACC 2004
SYNERGY: Clean patients
If all crossovers are taken out, there is no
difference in bleeding complications
"This is a retrospective look and needs to
be viewed with caution."
• 75% of patients were on prior
antithrombotic therapy
• In patients with no prior drug
exposure there was a 16%
benefit with enoxaparin
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: No prior treatment
Patients with no prior antithrombotic treatment
End points (%)
16
Enoxaparin
Unfractionated heparin
14.8
14
12.6
12
9.7
10
8
6.9
6
4
3.1
1.8
2
0
Death/MI
Heartbeat – March 2004
GUSTO severe
bleeding
TIMI major
bleeding
ACC 2004
ACC 2004
SYNERGY: Switching agents
"Postrandomization crossover--all that it
bought you was an excess of bleeding
complications."
Prerandomization switching seemed to
mask the effect of prior enoxaparin
"Do you wind up clouding your ability to
show a difference of the agents
because you've used one of those
agents beforehand?"
Heartbeat – March 2004
Ferguson
ACC 2004
SYNERGY: Summary
From the practical point of view
enoxaparin is a great drug
•Good feasibility with delayed
intervention
•Questions remain for acutely treated
patients
"This study really adds significantly
to our knowledge of LMW
heparin, which is coming on
stronger and stronger in the
cardiovascular field."
Heartbeat – March 2004
Fuster
ACC 2004
Sudden Cardiac Death in
Heart Failure Trial
SCD-HeFT
Heartbeat – March 2004
ACC 2004
SCD-HeFT: Design
• 2521 patients with NYHA class 2-3 HF
and LVEF <35%
• 148 centers in North America and New
Zealand
• Largest internal cardioverter defibrillator
(ICD) trial ever conducted
• ICD vs placebo
• Medium follow-up of 45 months
Heartbeat – March 2004
ACC 2004
SCD-HeFT: ICD patients
All patients
30
End point (%)
25
Nonischemic patients
Ischemic patients
27
23
21
20
15
10
5
0
Heartbeat – March 2004
Decrease in mortality risk
ACC 2004
ACC 2004
SCD-HeFT: Low ejection fraction
Before the trial it was unknown whether
MADIT II criteria would apply to
patients with low EF and dilated
cardiomyopathy.
"Now we can say that patients with
cardiac failure in class 2-3 with EF of
<35% do better on an ICD."
Heartbeat – March 2004
Fuster
ACC 2004
SCD-HeFT: Nonischemic patients
"A very exciting breakthrough."
The fact that nonischemic patients
achieved better results is very
exciting.
• Will set a new standard of cardiac
care for patients with low EF and no
known ischemia
Heartbeat – March 2004
Weber
ACC 2004
SCD-HeFT: Benefit from ICDs
"Long-awaited."
Patients with low EF are at great risk
for sudden death
• Tremendous benefit from ICD
therapy
• No benefit from amiodarone
therapy
Hopefully ICDs become cheaper
and can benefit more patients
Heartbeat – March 2004
Cannon
ACC 2004
SCD-HeFT: Clean patients
Sticky issue:
"We are not willing to pay for the standard
of care or allow the standard of care to
be utilized in our patients."
• We are rationing ICD therapy
• Criteria need to be expanded
for CMS to cover this
Heartbeat – March 2004
Ferguson
ACC 2004
SCD-HeFT: Two steps forward
Sudden cardiac death is a huge problem
• ICDs and automated external
defibrillators (AEDs) have been two
major steps forward
"Hopefully this very clear governmentsponsored trial will open the door to
greater use."
Heartbeat – March 2004
Cannon
ACC 2004
SCD-HeFT: Class-3 patients
Why didn't class-3 patients have the
same benefit as class-2 patients?
Fuster
In many class-3 patients the cause of
mortality may not be sudden death
but progression of disease, etc
"You can't lose sight of the primary
benefit."
Ferguson
Heartbeat – March 2004
ACC 2004
SCD-HeFT: Stratification
According to the study, defibrillators
should be put into HF patients in class
2 with low ejection fraction
Issue of concern:
The epidemic of cardiac failure is
going to drive the economics of this to
the sky
"The question is, how do
we stratify?"
Heartbeat – March 2004
Fuster
ACC 2004
SCD-HeFT: Greatest benefit
Risk stratification will be a great help
• Multivariate approach
• Sort out which patients will derive
the most benefit first
"Hopefully, again, we'll make a big
surge in the use of these very
important life-saving devices."
Heartbeat – March 2004
Cannon
ACC 2004
SCD-HeFT: Stratification criteria
No stratification on the basis of
• Ischemic vs nonischemic
• QRS duration
Criteria arbitrarily set up previously do not
work; therefore, new criteria need to
be developed.
Heartbeat – March 2004
ACC 2004
SCD-HeFT: Clinical practice
In view of these data, facing a patient
with
• Age 65
• EF 30%
• Dilated cardiomyopathy discovered
three years ago
• Class 3
Would you put in an ICD?
Heartbeat – March 2004
Fuster
ACC 2004
SCD-HeFT: Protective devices
"The vice president took one, and his EF
is substantially above that level."
• Sudden cardiac death is a majorleague problem in the US
• An ICD is a protective and helpful
device
• ICDs should be made available
to more and more people
Heartbeat – March 2004
Cannon
ACC 2004
SCD-HeFT: Two steps forward
After SCD-HeFT, in low-EF patients we
have to assume that there is the
potential for benefit
"I would be very inclined to put an ICD in
someone like that."
Heartbeat – March 2004
Ferguson
ACC 2004
Final thought: Fuster
PROVE-IT
Lowering LDL to 60-70 mg/dL is
efficacious
SYNERGY
LMWH is evolving slowly in
antithrombotic therapy
SCD-HeFT
striking results with ICDs in
patients with dilated
cardiomyopathy
Heartbeat – March 2004
Fuster
ACC 2004
Final thought: Ferguson
Simple questions in all trials:
•Is more intensive LDL lowering
good?
•Are LMWHs of benefit?
•Do ICDs work in this group?
"More important than the results is the
reason behind the results."
Heartbeat – March 2004
Ferguson
ACC 2004
Final thought: Cannon
"Steady progress in improving outcomes
has been the really wonderful and
encouraging message out of the ACC
2004."
Heartbeat – March 2004
Cannon
ACC 2004
Preview
Topics for part 2 of the ACC 2004
discussion panel:
•Rimonabant: How to quit smoking
and become thin
•Off-pump surgery
•Guidelines in Applied Practice (GAP)
projects
Heartbeat – March 2004
Fuster