Transcript Triumph of the trials

Triumph of the trials
Triumph of the trials: ACC 2002
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, New York
Christopher Cannon MD
Cardiologist
Brigham and Women's Hospital
Boston, Massachusetts
James Ferguson MD
Associate Director, Cardiology
St Luke's Episcopal Hospital and Texas Heart Institute
Houston, Texas
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Heartbeat – Apr 2002 Brooklyn, New York
Triumph of the trials
Subjects
MADIT II
ICDs for post-MI patients
with low EF
Atrial fibrillation
Rate vs rhythm
Coated stents
The end of restenosis?
Heartbeat – Apr 2002
Triumph of the trials
MADIT II
Multicenter Automatic Defibrillator
Implantation Trial II
1232 post-MI patients with moderate LV
dysfunction (EF 30%) randomized to ICD
or conventional medical therapy
Arrhythmia was not an inclusion criteria,
did not require previous EP testing
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: All-cause mortality
25%
P=0.016
20%
15%
19.8%
14.2%
10%
5%
0%
ICD
Heartbeat – Apr 2002
Medical therapy
Moss et al. N Engl J Med
2002;346(12):877-83.
Triumph of the trials
MADIT II: Additional discussion
Hospitalizations
ICD group had more
hospitalizations
Drug treatment
The patients received the
proper drug regimen
Cost
Do we put ICDs in everyone?
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Diverging curves
Time
Percent reduction
in rate of death on
ICD therapy
Nominal
95% CI
1 year
12
-47-20
2 years
28
4-46
3 years
28
5-46
Heartbeat – Apr 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
Triumph of the trials
MADIT II: Increased hospitalizations
Patient
group
Conventional
therapy group
Defibrillator
group
# patients
hospitalized
# patients
hospitalized/1000
hours follow-up
73 (14.9%)
9.4
148 (19.9%)
11.3
Nominal p=0.09
"If you save lives in sick people, they are going
to require more hospital resources."
Ferguson
Heartbeat – Apr 2002
Moss et al. N Engl J Med 2002;346(12):877-83.
Triumph of the trials
MADIT II: Medications
ICD
(n=742)
Medical
therapy
(n=490)
ACE-inhibitors
68%
72%
Beta-blockers
70%
70%
Statins
67%
64%
Diuretics
72%
81%
Medication at last
contact
Heartbeat – Apr 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
Triumph of the trials
MADIT II: Performance
We don't yet have
details on how often the
ICDs actually fired in the
patients.
VENTAK PRIZM 2 ICD
Source: Guidant
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Mortality by event
ICD
(n=742)
Medical
therapy
(n=490)
Noncardiac
26
20
Cardiac
74
67
27 (3.6%)
46 (9.4%)
41
18
Cause of death
Arrhythmic
Nonarrhythmic
Heartbeat – Apr 2002
Moss et al. N Engl J Med
2002;346(12):877-83.
Triumph of the trials
MADIT II: Fuster's hypothesis
"I bet that what is happening is
the group that otherwise might
have been induced into
ventricular tachycardia is the
group that has benefit."
Fuster
VENTAK PRIZM 2 ICD
Source: Guidant
Heartbeat – Apr 2002
Triumph of the trials
MADIT-II: MUSTT
Entry Criteria
Mortality at 5
years
Total mortality
Heartbeat – Apr 2002
• EF < 40%
• CAD
• spontaneous nonsustained
ventricular tachycardia (VT-NS)
ICDs
(n=161)
Drug therapy
(n=153)
P value
24%
55%
<0.001
Buxton et al. N Engl J Med
1999;341(25):1882-90.
Triumph of the trials
MADIT II: The patient
Patient with low EF, previous MI,
and the patient asked for a
defibrillator ICDs cost $2535,000
Found a normal result on signalaveraging, so I sent him home
VENTAK PRIZM 2 ICD
Source: Guidant
Heartbeat – Apr 2002
Fuster
Triumph of the trials
MADIT II: Risk stratification
"The idea of risk stratification to try and
identify those who benefit most has
become absolute dogma in clinical
practice in acute coronary syndromes."
•Inducibility makes sense as
a good marker of the risk of
arrhythmic death
•How recent is the MI?
•Arrhythmic burden might be
useful
Heartbeat – Apr 2002
Cannon
Triumph of the trials
MADIT II: True costs
•
We will eventually have to have risk
stratification
•
What is cost/quality of year of life saved?
•
We need data extending out for 2-3 years
Weber
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Science takes its course
"The truth is that whenever we do anything
that prolongs life we are going to be
rewarded by horrifying increases in cost.
And if we save them completely from
heart disease they are going to get
cancer."
"In a way it's a futile and frustrating
discussion."
Weber
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Extending the boundaries
What we're doing is defining the
boundaries of where ICDs work and don't
work
"What MADIT II has done is take the
stake and move it a little farther out in
terms of post-MI patients with low
ejection fraction."
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Drilling into the data
We will find a population that benefits
and a population that does not
Inducible VT is a completely reasonable
hypothesis for defining the benefit
population
Putting ICDs in everyone who qualifies
for MADIT is "potentially backbreaking"
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Signal-averaging
Used signal-averaging because it was a
strong predictor of high-risk in MUSTT
At this point in time, don't put an ICD in
patients who qualify for MADIT II who
have normal signal-averaging
"We have to face these patients today."
Fuster
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: QRS interval
QRS interval
Hazard ratio
< 0.12 sec
0.12-0.15 sec
>0.15 sec
0.2
0.4
0.6
0.8
Defibrillator
better
Heartbeat – Apr 2002
1.0
1.2
Conventional
therapy better
Moss et al. N Engl J Med 2002;346(12):877-83.
Triumph of the trials
MADIT II: Assessing patients
We don't have enough
information to predict who
will benefit most
"Seat of the pants indicators"
such as QRS intervals or the
number of extra systoles
should be helpful for now
VENTAK PRIZM 2 ICD
Source: Guidant
Weber
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Fundamental approach
"The fundamental approach that one
takes with these patients is 'are they
guilty until proven innocent' or are they
'innocent until proven guilty'?"
"Am I going to put a defibrillator in this
guy unless there is a reason not to or do
I require a reason to put a defibrillator in
this individual?"
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Reasons to put an ICD in
"I still need a reason to put a defibrillator
in an individual."
• Signal-averaged ECG
• Frequency of VPDs
• Heart-rate variability is a possibility
• Probably would not take someone to
provocative EP testing
Heartbeat – Apr 2002
Ferguson
Triumph of the trials
MADIT II: Cost
MADIT II entry criteria would lead
to an additional 300,000
patients for ICDs, a $9 billion
market
ICDs cost $25-35,000
"When you have something good,
industry competes and costs go
VENTAK PRIZM 2 ICD
down."
Source: Guidant
Fuster
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Cheaper ICDs
As demand grows, costs should drop
These ICDs are the "BMW 7-series"
versions, with all the hi-tech bells and
whistles
Cheaper, simpler ICDs could be used in
patients with uncomplicated arrhythmic
history
Cannon
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Lay press concerns
Extending Life, Defibrillators
Can Prolong Death
Could we unintentionally torture
patients with ICDs?
Rare, but not impossible
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Quality of Life
While making guidelines, everyone said that
AFFIRM and RACE would give all the answers
"I was disappointed"
The issue is quality of life, not mortality, but that
wasn't studied
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM design
Atrial Fibrillation Follow-up Investigation
of Rhythm Management
Conducted at 213 centers in the US and
Canada
Randomized 4060 patients to rate control
therapy or to rhythm control therapy
All patients enrolled in the trial were able
to tolerate either rate or rhythm control
therapy at baseline
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: AFFIRM results
Endpoint
Rate
control
Rhythm
Control
P value
Mortality
306
356
0.058
79
84
NS
Stroke
Wyse DG, ACC 2002
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: RACE design
RAte Control vs Electrical cardioversion for
persistent atrial fibrillation (RACE)
522 patients randomized to medical rate
control (n=256) or electrical cardioversion
rhythm control (n=266)
3 years follow-up
Primary endpoints: morbidity and mortality
Secondary endpoints: quality of life and cost
of therapy
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: RACE results
Endpoint
Combined mortality
and morbidity*
Cardiovascular
mortality
Rate
control
(n=256)
Rhythm
Control
(n=266)
17.2%
22.6%
7.0%
6.7%
*cardiovascular death, hospitalization for heart failure,
thromboembolic complications, severe bleeding, pacemaker
implantation, or severe drug side effects
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : No answers
My original question wasn't answered
Patients with systolic or diastolic
dysfunction who don't have atrial kick
weren't included in the study
Fuster
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Disappointing
"I'm not an electrophysiologist, so I've
been waiting for guidelines to tell me
what to do for some time."
"It's a little disappointing that […] those
people who might have benefited
probably didn't even get into the study."
Weber
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM drugs
Rhythm control
• amiodarone (39%)
• sotalol (33%)
• propafenone (10%)
Ablation and pacemakers were given in the
rhythm arm, if necessary
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM drugs
Rate control
• digoxin (51%)
• beta-blockers (49%)
• calcium-channel blockers (41%)
There was no specific drug regimen
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Drug safety
"At least the drugs that maintained normal
sinus rhythm didn't kill the patients."
Maybe amiodarone is protective
Fuster
It could be that the fact these were
patients with atrial fibrillation played a
role
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: Low mortality
Patients who need atrial kick are the
toughest atrial fibrillation patients to
work with
The good news is mortality favored rate
control slightly – this looks pretty safe
Cannon
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: Warfarin
"I came away with the notion that A-Fib
and coumadin are very good partners."
Most strokes in AFFIRM occurred in
patients who either stopped warfarin or
had an INR below 2.0
The idea you should convert A-Fib patients
so they can get off anti-coagulation
doesn't hold up
Heartbeat – Apr 2002
Cannon
Triumph of the trials
Atrial fibrillation : Anticoagulation
"The concept that you convert to normal
sinus rhythm and therefore off of
anticoagulants is really a dream."
I do Holter monitoring 3 months later
because most patients you can see
there are still a few beats of atrial
fibrillation
Fuster
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: Anticoagulation
Atrial fibrillation developing after cardiac
surgery often reverses itself
You should still follow up patients with a
Holter to document that the patient has
stable sinus rhythm
Cannon
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: Guidelines
The guidelines urge great caution about
discontinuing anticoagulants
You should continue anticoagulation unless
something convinces you otherwise
ACC/AHA/ESC GUIDELINES FOR THE MANAGEMENT OF
PATIENTS WITH ATRIAL FIBRILLATION
J Am Coll Cardiol 2001;38:1266i-1xx
Heartbeat – Apr 2002
Fuster
Triumph of the trials
Atrial fibrillation: Anticoagulation
"The big winner in this seemed to be
coumadin. Because if you want to use
rhythm control because you think you
are reducing the need for
anticoagulation you're probably making
a mistake."
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: FIM
Measurement
at 24 months
Fast release
formula
Slow release
formula
Late loss
0.32 mm
-0.09 mm
Restenosis rate
0%
0%
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: RAVEL
Measurement at
12 months
Sirolimus
(n=??)
Control (n=??)
Event-free
survival
94.2%
71.2%
Late loss
-0.01 + 0.33
0.80 + 0.53
Restenosis rate
0%
26%
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: Stopping cell growth
"[Ending restenosis] is an idea people have
been looking for, and stopping cell
growth locally looks like a real winner."
Cannon
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: Stopping cell growth
"It's probably a victory for vascular
biologists everywhere to say the
shotgun approach or crude approaches
we've used in the past have not
worked."
Not all coated stents will work, we need to
look long at hard at the data
We need to look at the SIRIUS trial
Heartbeat – Apr 2002
Ferguson
Triumph of the trials
Coated stents: Early pathology
Brazil data makes you believe the
subsequent pathology is determined at
the time of procedure
"I assume most of the value of the coated
stent is a local effect that takes place
soon after the stent is put in."
Heartbeat – Apr 2002
Weber
Triumph of the trials
Coated stents: New study
>2000 pts
Diabetics with multi-vessel disease
lesions (15-30 mm long, 2.5-3.5 mm
diameter)
Randomized to sirolimus stent or CABG
This study has been submitted to NIH and
is under consideration
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: End of CABG?
Finding clinical effect on high-risk patients
is the most important study to do
•
BARI used balloon angioplasty without
antiplatelet therapy
•
Can diabetics with multi-vessel disease
be stented or must they use surgery?
•
It even raises questions about stenting
patients with stable angina
Heartbeat – Apr 2002
Cannon
Triumph of the trials
Coated stents: 6-month QCA in
diabetics
Measurement
Sirolimus
(n=19)
Control (n=25)
P value
Mean luminal
diameter
2.31 mm
1.56 mm
<0.0001
Late loss
0.08
0.82
<0.0001
Diameter stenosis
16%
38%
<0.0001
Restenosis rate
0%
42%
<0.0001
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: Patient
What do you do with this patient?
• Had 3 previous PCIs in the circumflex
artery
• Currently has a 1.5-cm lesion in the
circumflex artery
Do you send him to Europe to get the
sirolimus-coated stent or do you use
radiation?
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: Radiation advantage
I would go with beta-radiation therapy
•
Reduces in-stent restenosis by about
50%
•
Coated stents have not shown favorable
results for in-stent restenosis
Heartbeat – Apr 2002
Cannon
Triumph of the trials
Coated stents: Radiation questions
Some issues still need to be answered with
radiation therapy
"What are you doing to the biology of the
vessels and do you change how they are
going to respond in the future if in fact
you don't prevent restenosis?"
Heartbeat – Apr 2002
Ferguson
Triumph of the trials
Conclusions: Subjects
MADIT II
ICDs for post-MI patients
with low EF
Atrial fibrillation
Quantity and quality of life
Coated stents
The end of restenosis?
Heartbeat – Apr 2002
Triumph of the trials
Conclusions: Ferguson
Coated stents
Marrying mechanical approach
and an understanding biology
Atrial fibrillation
Rhythm control doesn't
mean you stop anticoagulation
ICDs
Point out our need to apply
techniques of risk stratification
Heartbeat – Apr 2002
Ferguson
Triumph of the trials
Conclusions: Weber
Coated stents
It won't be long before the
coated stent is the only way
to go
Atrial fibrillation
One word: coumadin
ICDs
We still need to learn more
about which patients are
the best subjects
Heartbeat – Apr 2002
Weber
Triumph of the trials
Conclusions: Cannon
A triumph for trials guiding appropriate
therapy
Ventricular tachycardia: Devices
Coronary stenosis: Devices and medicine
married together
Atrial fibrillation: Medicine is the right
answer
Heartbeat – Apr 2002
Cannon
Triumph of the trials
Conclusions: Fuster
It's an exciting time, but how much could
we accomplish if we could move
forward even more in primary
prevention?
Fuster
Heartbeat – Apr 2002