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Heartbeat – ACC 2006
ACC 2006 part 2: Where's the
controversy?
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Christopher Cannon MD
Staff cardiologist
Brigham and Women's Hospital
Boston, MA
Melissa Walton-Shirley MD
Cardiologist
TJ Samson Community Hospital
Glasgow, KY
Heartbeat – ACC 2006
Four controversial studies
from the recent ACC meeting
ASTEROID
• A Study to Evaluate the Effect of Rosuvastatin on
Intravascular Ultrasound-Derived Coronary Atheroma
Burden
UNLOAD
• Ultrafiltration versus Intravenous Diuretics for Patients
Hospitalized for Acute Decompensated Heart Failure
BASKET-LATE
• Basel Stent Cost-Effectiveness Trial–Late Thrombotic
Events
MIST
• Migraine Intervention with STARflex Technology
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Study design
Between November 2002 and October 2003,
507 patients were enrolled in this intravascular
ultrasound (IVUS) study
All patients were treated with 40-mg
rosuvastatin daily
There was no control group
Participants were followed for 24 months, at
which time they were reevaluated with IVUS
Baseline and 24-month IVUS data were
available for 349 patients
Nissen SE. ACC 2006 Scientific Sessions;
March 13, 2006; Atlanta, GA. Abstract 411-8.
Nissen SE, et al. JAMA 2006;295:1556.
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID:
Lipid results (mean values)
Baseline
After 24
months of
treatment
%
change*
Total cholesterol
(mg/dL)
204
133.8
–33.8
LDL-C (mg/dL)
130.4
60.8
–53.2
HDL-C (mg/dL)
43.1
49.0
+14.7
Triglycerides (mg/dL)
152.2
121.2
-14.5
LDL-C/HDL-C ratio
3.2
1.3
–58.5
*p<0.001 for all comparisons between baseline and during treatment
Heartbeat – ACC 2006
ASTEROID: Primary efficacy
parameters
The mean change in the percent of
atheroma volume was borderline because
it was of an entire vessel
• Average decrease in volume was 3.1%
Results were significant at p=0.001
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Conclusions
It appears that 40-mg rosuvastatin daily
not only prevented progression of the
disease but also slightly enhanced
regression
However
• The patient population was not high risk.
• There was no control group.
• The changes are minimal.
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Exciting results
The results really match up nicely with everything we
know
There are limitations to the study
• Not having a control group
Results show
• Intensively modifying lipids has a dramatic effect
on LDL-C levels
• A trend toward a significant (15%) increase in
HDL-C
For the first time in a single statin study, these
factors are shown to be important in the regression
of plaque
Christopher Cannon
Heartbeat – ACC 2006
ASTEROID: Goals of therapy
This study is not too different from the GREACE
study
• Lower the LDL-C as much as possible
• Raise the HDL-C as much as possible
Rosuvastatin does just that
There is no progression of disease over 24
months, which is very attractive
GREACE: Athyros VG et al. J Clin Pathol 2004;57:728.
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Tempered
enthusiasm
Rosuvastatin is not an equal-opportunity therapy
• Many patients cannot tolerate statins at any dose
• Even more patients cannot afford statins
• Some patients are noncompliant
Will physicians subconsciously push patients who
are suffering from myalgia or other side effects to
stay on statins?
Future studies should include strategies aimed at
improving tolerability
• Simultaneous coenzyme-Q10 use
• High-dose pulse therapy
Melissa Walton-Shirley
Heartbeat – ACC 2006
ASTEROID: Patient population
Issues important to the general clinician
• Patients in this study did not necessarily have
significant progression
• There was no control group
• Only 13% of the patients had diabetes
• A large proportion of patients just had
unstable angina
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Figure 3
Relationship between mean LDL-C levels and
median change in percent atheroma volume for
several intravascular ultrasound trials
Mean change in percent
atheroma volume, %
1.8
CAMELOT
placebo
1.2
0.6
0
REVERSAL
atorvastatin
A-Plus
placebo
–0.6
–1.2
50
ASTEROID
rosuvastatin
60
REVERSAL
pravastatin
70
80
90
100
Mean LDL-C (mg/dL)
Nissen SE, et al. JAMA 2006;295:1556.
r2=0.97
p<0.001
110
120
Heartbeat – ACC 2006
ASTEROID: Limitations
The different duration of this trial makes comparison
difficult
• ASTEROID was 24 months
• Previous IVUS studies done by Nissen et al were
18 months
Measuring atherosclerosis in different patient
populations makes comparisons difficult to interpret
• People with not-too-severe atherosclerosis
• Higher-risk patients
Although this trial has limitations, the results seem
to fit with everything we know about intensive statin
therapy
Christopher Cannon
Heartbeat – ACC 2006
ASTEROID: Data needed
REVERSAL used IVUS to show that lowering LDL-C
significantly with atorvastatin stopped the
progression of disease in a relatively high-risk
population
PROVE IT–TIMI 22 showed that there were
significantly fewer cardiovascular events with
atorvastatin
ASTEROID showed that rosuvastatin is very effective
in modifying lipid profiles and in preventing
progression of disease and maybe some regression
• However, there are no clinical data correlating
rosuvastatin and IVUS
REVERSAL: Nissen SE et al. JAMA 2004; 291:1071.
Valentin Fuster
Heartbeat – ACC 2006
JUPITER trial
Justification for the Use of Statins in Primary
Prevention: An Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial
• More than 9000 patients enrolled
• Lower-risk population
• A primary-prevention trial
• Positive C-reactive protein (CRP) as an entry
criterion
JUPITER results are probably two years away, but
clinical data are coming
Christopher Cannon
Ridker PM et al. Circulation 2003;108:2292-2297
Heartbeat – ACC 2006
Rosuvastatin: Side effects?
A few months ago, there was a lot of
discussion about whether rosuvastatin
caused side effects
• What was reported
• What was not reported
Valentin Fuster
Heartbeat – ACC 2006
The trouble with statins
Simvastatin becomes generic in late 2006
We don't know whether data from simvastatin
translate or extrapolate to other statins
Patients are still reluctant to take statins
• It's up to the practitioner to convince patients
that statins are safe as long as they monitor
side effects and communicate with their
practitioner
Melissa Walton-Shirley
Heartbeat – ACC 2006
ASTEROID: Summary
There are many people who should be taking
statins that are not
• We must look for strategies to increase their
use
ASTEROID trial
• 40 mg rosuvastatin daily proves that lower
LDL-C and higher HDL-C is better
• Some degree of regression was shown over
24 months
Valentin Fuster
Heartbeat – ACC 2006
ASTEROID: Key message
In five years, our LDL-C target in a high-risk
population will probably be around 50
mg/dL
One of the messages from ASTEROID is that
lower is better
Christopher Cannon
Heartbeat – ACC 2006
LDL-C target in five years
Prediction
• An LDL-C of 50 mg/dL in a high-risk
population
• An LDL-C of 75 mg/dL in a lower-risk
population
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Study design
200 patients with acute decompensated heart failure
at 28 institutions
Randomized to either
• Peripheral ultrafiltration using a commercially
available system
• Standardized IV diuretic therapy
Patients were evaluated at 48 hours and at 90 days
Patients required up to two sessions of ultrafiltration
over a period of a couple of days
• 4 L of fluid were removed in each eight-hour
session
• A total of 8 L of fluid were removed altogether
Costanzo MR et al. ACC 2006 Scientific Sessions;
March 14, 2006; Atlanta, GA. Abstract 418-7.
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Results
Fewer patients in the ultrafiltration group than
in the diuretic-treated group subsequently
required vasoactive drugs at 90-day follow-up
The ultrafiltration group did better
• More fluid lost in the first 48 hours.
• Potassium levels were more stable.
• No increase in creatinine levels.
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Results at 90 days
Rehospitalization at 90 days:
• 18% of the ultrafiltration group.
• 32% of the diuretic-treated group.
Number of rehospitalization days:
• 1.4 days in the ultrafiltration group.
• 3.8 days in the diuretic-treated group.
Emergency-room visits:
• 21% in the ultrafiltration group.
• 44% in the diuretic-treated group.
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Questions
Do all these patients need ultrafiltration?
Were diuretics used appropriately in UNLOAD?
• Resistance to diuretics such as Lasix
[furosemide] can develop
Is ultrafiltration necessary, or could diuretics,
which are much cheaper, be used more
effectively?
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Effect on therapy
Of all the data that were presented at ACC 2006,
the UNLOAD findings have the greatest potential
to affect acute hospital-based therapy
From a clinical standpoint, ultrafiltration allows
patients to fit into their shoes and to go home
with the same creatinine levels they came in with
This was a natural next step for cardiologists
dealing with CHF
• It is nearly impossible to motivate
nephrologists to manage fluid in the nonuremic
patient
Melissa Walton-Shirley
Heartbeat – ACC 2006
UNLOAD: Cost effectiveness
Reducing the cost of DRG 127 [heart failure and
cardiac shock] is the holy grail of CHF
management
The $19 000 this device costs is a pittance
compared with other technology purchases
hospitals make
Shortening the length of hospital stay and
preventing readmission of just two patients
pays for the device
Melissa Walton-Shirley
Heartbeat – ACC 2006
UNLOAD: Cost of ultrafiltration
Each ultrafiltration session costs close to $1000
Decreasing the number of hospital days and the
number of visits to the emergency room saves
money
Despite being somewhat expensive, is
ultrafiltration cost effective?
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Cost effective
We have to be careful not to buy into the "just-plugthem-into-a-machine" mentality
Ultrafiltration should not replace good dietary
instruction and fluid restriction
We should take a hard look at the medical regimen of
volume-overloaded patients
• Are we doing anything to offend them?
• Are we keeping them on dihydropyridine calciumchannel blockers?
• Do we have them on glitazones (which, for some
patients, means a 40-lb weight gain)?
We must carefully select which patients are offered
ultrafiltration
Melissa Walton-Shirley
Heartbeat – ACC 2006
UNLOAD: Diuretic
resistance
When I see a patient on a dose of Lasix over
300 mg, I drop the dose and prescribe
Zaroxolyn [metolazone]
• In general, there is a significant change in the
diuresis of these patients
Ultrafiltration is a significant move forward, but
I'm not convinced that most of the patients we
see on a daily basis need this device
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Heart failure
As coronary disease is treated successfully in
more and more patients, more and more patients
are left with heart failure
Diuresis takes an enormous amount of time
Ultrafiltration offers another option to people
on high doses of Lasix who are still fluidoverloaded
• The savings in length of hospital stays and
rehospitalizations leads to an overall cost
benefit
A formal cost-effectiveness analysis is still needed
Christopher Cannon
Heartbeat – ACC 2006
UNLOAD: Chemistry
Why does all the chemistry continue to be
fantastic, even after 8 L of fluid is removed?
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Chemistry explained
The fluid that's removed is isotonic, so there's
no activation of the renin angiotensin system
There was not a lot of hypotension in UNLOAD
patients so, unfortunately, patients left the
hospital feeling about the same, with shortness
of breath
• However, they could wear their clothing and
had significant weight loss, which is really the
goal for these patients
The reason for the lack of improvement in
dyspnea is unclear
Melissa Walton-Shirley
Heartbeat – ACC 2006
UNLOAD: A significant advance
Ultrafiltration is a significant advance for
patients with significant cardiac failure and
volume load
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD: Nesiritide alternative
Ultrafiltration is a perfect solution for patients
excluded by the nesiritide-clinic situation
Our nesiritide clinic, which ran for several
months, was closed when the controversy
began
Patients who no longer have access to the
nesiritide clinic on a weekly basis are looking
forward to trying this device
Melissa Walton-Shirley
Heartbeat – ACC 2006
BASKET LATE: Study design
The original BASKET trial randomized a relatively
complex patient group to a bare-metal stent or to a
drug-eluting stent, either paclitaxel (Taxus) or
sirolimus (Cypher)
BASKET LATE followed 746 BASKET patients who
were free of major adverse coronary events (MACE)
at six months for an additional 12 months
Pfisterer ME et al. ACC 2006 Scientific Sessions;
March 14, 2006; Atlanta, GA. Abstract 422-11.
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE: Study design
Thrombosis-related events in the two groups (baremetal or drug-eluting stents) were compared
• Thrombosis-related events comprised
angiographically confirmed stent thrombosis,
sudden cardiac death, and target-vessel
myocardial infarction
Pfisterer ME et al. ACC 2006 Scientific Sessions;
March 14, 2006; Atlanta, GA. Abstract 422-11.
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE: Results
MACE rates were no different between the baremetal and drug-eluting stent groups
The rates of nonfatal MI plus cardiac death and
of nonfatal MI alone were significantly higher
with drug-eluting stents than with bare-metal
stents
• Nonfatal MI: 4.1% in the drug-eluting-stent
group vs 1.3% in the bare-metal-stent group
• Cardiac death and nonfatal MI: 4.9% in the
drug-eluting-stent group vs 1.3% in the baremetal-stent group
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE: Surprising
results
The design of BASKET LATE led to a unique
opportunity to look at planned discontinuation
of clopidogrel six months after stent placement
The dramatic findings have immediate
implications
• They aren't definitive because only ~100
patients were studied, but the data are
compelling
Christopher Cannon
Heartbeat – ACC 2006
BASKET LATE and clopidogrel
What does the fact that most of the BASKET
LATE patients stopped taking clopidogrel at
six months tell us?
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE: Clopidogrel
debate
This study shows that discontinuation of clopidogrel
six months after drug-eluting-stent placement is not a
good idea
Package-insert information, based on the elective singlevessel stenting that earned these stents initial approval:
• Taxus stent: Clopidogrel for six months
• Cypher stent: Clopidogrel for three months
The BASKET LATE population comprised high-risk patients
at high risk for recurrent events
Many interventionalists are considering two years of
clopidogrel to prevent stent thrombosis related to drugeluting stents
This study will extend the duration of clopidogrel
treatment after drug-eluting-stent placement
Christopher Cannon
Heartbeat – ACC 2006
BASKET LATE: The trade-off
In 100 patients with drug-eluting stents:
• Five restenotic phenomena will be prevented.
• There will be 3.3 late deaths from MI.
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE: Implications
After seeing a couple of case reports in the
literature of late and ultralate thrombosis (one
of which was 18 months out), I started advising
patients who have received drug-eluting stents
to stay on clopidogrel indefinitely
These results are concerning because many
patients cannot afford a year's worth of
clopidogrel
At our facility, 100% of the patients who are
implanted are STEMI patients, who are at
higher risk
Melissa Walton-Shirley
Heartbeat – ACC 2006
BASKET LATE: Choosing a
stent
It's not the up-front cost of the stent anymore that
determines which stent will be used, it's the ability of
the patient to pay for the long-term Plavix prescription
and the expectation of compliance by the patient
We need to do a better job of taking a good general
medical review of systems before stent implantation
• Many patients are coming back within three months
of implant needing a cholecystectomy or with gut
bleeding
We need to do a better job of defining who should and
who should not get a drug-eluting stent
• A patient who knew he was facing a biopsy for a
chest mass received a drug-eluting stent when he
underwent PCI
Melissa Walton-Shirley
Heartbeat – ACC 2006
BASKET LATE:
Appropriate use of clopidogrel
Based on this study, perhaps we should
prescribe clopidogrel for 18 to 24 months
The significant drop in the rate of restenosis
means we should not discount drug-eluting
stents
• Perhaps the appropriate use of clopidogrel
over a longer period of time is required
Valentin Fuster
Heartbeat – ACC 2006
BASKET LATE:
Clopidogrel and surgery
The preprinted letter that comes from the surgeon
advising patients to stop all anticlotting drugs for 10
days before surgery must be carefully considered
We may need to time clopidogrel more like warfarin
• New data suggest discontinuing clopidogrel three
days before surgery and then monitoring the level
of platelet inhibition so that people are not putting
themselves at risk for thrombotic events by
discontinuing clopidogrel
Christopher Cannon
Heartbeat – ACC 2006
MIST: Study design
147 migraine patients, between 18 and 60 years,
previously found to have a patent foramen ovale (PFO)
All patients were refractory to at least two classes of
migraine medications and had a one-year history of
migraine
All patients had contrast transthoracic
echocardiography to establish shunt size
• Half were treated with a PFO closure device
implantation, the STARflex septal-repair implant
• Half underwent a sham procedure consisting of
general anesthesia and a groin incision
All patients were prescribed aspirin and clopidogrel for
three months
Taaffe M. ACC 2006 Scientific Sessions;
March 12, 2006; Atlanta, GA. Abstract 945-109.
Valentin Fuster
Heartbeat – ACC 2006
MIST: Results
Three patients in each arm achieved the primary end
point—complete cessation of headaches
More PFO-closure than sham patients had a 50% or
greater reduction in headache days
• 42% of PFO-closure patients vs 23% of sham
patients achieved a 50% reduction in headache
days
More PFO-closure than sham patients had a
reduction in headache burden (calculated as
headache frequency × duration)
PFO closure might help headaches by preventing
platelets from releasing serotonin, which causes
headaches
Valentin Fuster
Heartbeat – ACC 2006
MIST: Jury still out
I sent a patient two years ago for PFO closure who
presented with a transient neurologic deficit; she
happened to also have a history of severe migraines
• She was 100% migraine free immediately after the
procedure and continues to be two years later
The presenters have not yet finished the calculations for
the shunt data, and therein might lie the explanation
• These patients had exceptionally large communications;
if the closures were not complete, improvement would
not be expected
Any migraine sufferer would jump at the chance for a 50%
reduction in the number of headaches or the number of
trips to the emergency room
It would be nice if the primary end point in MIST II were
the reduction in migraines instead of a cure
Melissa Walton-Shirley
Heartbeat – ACC 2006
MIST: Cause of headaches
Are platelets crossing the PFO and getting
into the head and releasing serotonin,
which causes the headaches?
Valentin Fuster
Heartbeat – ACC 2006
MIST: More data needed
The pathophysiology explaining this is unclear
If data from MIST II are consistent, then the
two trials together would show this benefit
One concern about PFO or atrial septal-defect
closure is with fractured parts of the devices
causing strokes
• Is this device different than atrial septaldefect closure devices?
We need to see all the safety data, beyond half
of 147 patients
Christopher Cannon
Heartbeat – ACC 2006
MIST: Course of action
If a patient presents tomorrow with
constant headaches and a PFO, would you
close it?
Valentin Fuster
Heartbeat – ACC 2006
MIST: Go with PFO closure
Patients who are completely incapacitated by
headaches and who are refractory to two or
three different therapies would jump at any
chance for relief
Because safety data for the closure device are
good, I'd recommend the procedure
Melissa Walton-Shirley
Heartbeat – ACC 2006
Summary: ASTEROID
ASTEROID
• 40-mg rosuvastatin daily
• LDL-C reaching an average of 60 mg/dL
• HDL-C increase of 15%
• No progression seen with IVUS
• Possibly some regression
A great study moving us toward lower LDL-C
In the future, in the high-risk population, LDL-C
targets may be as low as 50 mg/dL
Valentin Fuster
Heartbeat – ACC 2006
Summary: UNLOAD
UNLOAD: Ultrafiltration vs diuretics in patients
with decompensated heart failure
• Great chemistry
• No decrease in potassium
• No change in creatinine
• Fewer rehospitalizations
Ultrafiltration is cost effective
• It is worth it to pay $1000 for each of
two ultrafiltration sessions because of the
reduction in length of hospital stay and in
rehospitalizations
Valentin Fuster
Heartbeat – ACC 2006
Summary: BASKET LATE
In BASKET LATE, there was a higher incidence
of MI and sudden death related to thrombosis
with a drug-eluting stent than with a baremetal stent
When drug-eluting stents are used, continuing
clopidogrel for more than six months should be
considered
• Clopidogrel should probably be taken for 18
to 24 months
Valentin Fuster
Heartbeat – ACC 2006
Summary: MIST
In patients with recurrent headaches and a
PFO, closing the PFO decreases by 50% the
headache burden of these patients
Valentin Fuster
Heartbeat – ACC 2006
UNLOAD and CHF patients
More patients with congestive heart failure
than with acute MI present every day to
emergency rooms around the country
The UNLOAD data will likely affect the
largest number of patients
Melissa Walton-Shirley
Heartbeat – ACC 2006
Four good studies
ASTEROID reinforces the benefit of intensive
statin treatment
BASKET LATE reinforces the duration of
clopidogrel treatment of at least one year in
ACS or PCI patients
UNLOAD provides a terrific new option for the
large number of patients with severe heart
failure
Data from the closure of PFOs look intriguing;
we await the data from MIST II to see whether
they support the results from MIST
Christopher Cannon