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
Christopher M O'Connor MD
Associate Professor of Cardiology
Duke University Medical Center
Durham, NC
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Heartbeat – May 2002Brooklyn, New York
Triumph of the trials
Subjects
DANAMI-2
Transferring patients for PCI
LIFE
Losartan for hypertension
WIZARD
Antibiotics for coronary
disease
Heartbeat – May 2002
Triumph of the trials
DANAMI-2
DANish multicenter Trial in Acute
Myocardial Infarction 2
1572 patients randomized to fibrinolysis
(100 mg front loaded tPA)or PCI + stent
Referral hospitals: tPA or ambulance
transfer to center for PCI
PCI centers: tPA or PCI
Primary endpoint: Death, reinfarction, or
disabling stroke in 30 days
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Inclusion criteria
ST-elevation 4 mm
Symptoms  12 hrs at randomization
Transfer  3 hrs from referral hospital to
cath-lab
Maximum transport distance 95 miles
Mean transport distance 35 miles
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: New PCI centers
5 PCI centers
24 referral hospitals
(62% of Danish population)
"In fact, one of the most interesting
aspects of this study was that the
Danish institutions didn't have PCI a
few years ago, so they had to be
trained."
Heartbeat – May 2002
Fuster
Triumph of the trials
DANAMI-2: Strategies of care
"I think this is an extremely important trial
because it not only addresses an
important scientific question but it also
looks at strategies of care."
O'Connor
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Raising the bar
"They raised the bar in doing this study [in
that] they geared up a system to try
and extend the reach of primary
angioplasty so that it would be possible
to offer this for people as far away as
30 or 50 miles."
Cannon
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Important to US
"What people forget is that even here in
the United States we don't all have an
interventional lab next door or around
the corner. In California you might
find an interventional lab in every
cardiologist's backyard or garage but
here in New York we don't have that
at all."
Weber
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Event rate
PCI
14%
p=0.0003
12%
10%
Fibrinolysis
13.7
p=0.35
7.6
6.6
8.0
p<0.0001
8%
6%
6.3
p=0.15
4%
1.6
2%
0%
Combined
Heartbeat – May 2002
Reinfarction
1.1
2.0
Stroke
Death
ACC 2002
Triumph of the trials
DANAMI-2: Government
involvement
"How striking it is how a decision
made by the government in
running a trial like this […] in
order to better serve people
from the health point of view."
Denmark
Heartbeat – May 2002
Fuster
Triumph of the trials
DANAMI-2: Mortality benefit
8.0%
"[The 1% absolute benefit] is as
big a difference as we saw
between tPA and streptokinase
a few years ago.
7.0%
6.0%
5.0%
"This is far more compelling than I
would ever have anticipated."
4.0%
3.0%
Weber
2.0%
1.0%
0.0%
Death
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Treatment strategy
"This isn't casual angioplasty versus
thrombolysis but in order to offer or
expect the benefits of this strategy you
really have to gear things up and do
rapid angioplasty."
"Making a real commitment to the strategy
will be the key to its success."
Cannon
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Logistical problems
The great transfer success is because of an
integrated system
Could the US adopt a system where a single
phone call starts the system up at another
hospital?
Fuster
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Committing to a system
"If we're going to make this effective
therapy […], we have to have protocols in
place just like we have a protocol to do a
clinical trial, we have to follow the
protocol and people have to think of the
care they are delivering like a clinical
trial."
O'Connor
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: 12-hour window
Primary end point
PCI
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
0-1.5
Fibrinolysis
>1.5-2.5
>2.5-4
>4-12
Time to randomization (hours)
Heartbeat – May 2002
DANAMI-2 site
Triumph of the trials
DANAMI-2: Busy cath-labs
If we accept these results, won't there be a
tendency for EMS and referring doctors to bypass
any hospital without PCI?
Weber
It's very likely, but with only 10-15% of hospitals
having cath-labs available, it will be very busy
At least we seem to have a 12-hour window for the
PCI
Fuster
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Resistance
"In our health system, finances drive a lot
of the way these patients are allocated to
hospitals. And because the MI patient is a
high-DRG diagnosis there is going to be
some resistance, unfortunately, unless
we can tie quality and outcomes to the
care of these patients."
O'Connor
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Economics
"How expensive is it going to be to prepare
institutions to be ready for these kinds
of transfers?"
Fuster
"In figuring out the real costs we have to
go beyond the acute event and see
what happens over the next few days
and the next few weeks."
Weber
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Summary
It is feasible to transfer patients in a
reasonable window of time
It will require a community-wide
commitment in order to make this happen
Is that commitment possible economically?
Fuster
Heartbeat – May 2002
Triumph of the trials
DANAMI-2: Costs
Costs are similar for thrombolysis and PCI
since many thrombolysis patients go on to
get PCI later
Receiving hospitals like more patients so
there is not a burden
The fear is that the referral hospitals will lose
not just the ST-elevation patients but all
chest pain patients
Heartbeat – May 2002
Cannon
Triumph of the trials
DANAMI-2: Boston pilot study
We have to have the protocol of 12-lead ECG
in field to target specifically the STelevation patients
We are changing the paradigm from going to
the nearest acute hospital to going to the
nearest primary angioplasty hospital
A 5- or 6-year process
Heartbeat – May 2002
Cannon
Triumph of the trials
LIFE: Inclusion Criteria
Losartan Intervention For Endpoint reduction in
hypertension
• 9193 patients
• Age 55-80 years
• Previously treated or untreated hypertension
• Systolic BP 160-200 mmHg or diastolic BP 95-115
mmHg
• ECG LVH
Cornell Voltage Duration Product >2440 mm*msec
(6-mm gender adjustment in women)
Sokolow-Lyon >38 mm
Heartbeat – May 2002
Triumph of the trials
LIFE: Hypothesis
If two drugs lower the blood pressure
equally but one causes LVH regression,
is one superior in preventing CV
events?
Primary composite endpoint of
cardiovascular morbidity and mortality,
defined as stroke, MI or cardiovascular
death
Losartan vs atenolol
Heartbeat – May 2002
Triumph of the trials
LIFE: Primary Composite Endpoint
Proportion of patients with first event (%)
16
Intention-to-Treat
14
Atenolol
12
Losartan
10
8
6
4
Adjusted Risk Reduction 13·0%, p=0.021
Unadjusted Risk Reduction 14·6%, p=0.009
2
0
Study Month
Losartan (n)
Atenolol (n)
0
4605
4588
6
4524
4494
Heartbeat – May 2002
12
4460
4414
18
4392
4349
24
4312
4289
30
4247
4205
36
4189
4135
42
4112
4066
48
4047
3992
54
3897
3821
60
1889
1854
66
901
876
Dahlof et al. Lancet 2002;359:995-1003
Triumph of the trials
LIFE: Fatal/Nonfatal Stroke
Proportion of patients with first event (%)
8
Intention-to-Treat
7
Atenolol
6
Losartan
5
4
3
2
Adjusted Risk Reduction 24·9%, p=0.001
1
0
Unadjusted Risk Reduction 25·8%, p=0.0006
0
6
12
18
24
30
36
42
48
54
60
66
Study Month
Heartbeat – May 2002
Dahlof et al. Lancet 2002;359:995-1003
Triumph of the trials
LIFE: Additional points
Blood pressure drop was the same in both
groups
LVH regressed in roughly 1/3 of patients
in losartan group
New onset of diabetes reduced by 25%
Heartbeat – May 2002
Triumph of the trials
LIFE: Head-to-head winner
"The first time that, head-to-head, one
anti-hypertensive drug has beaten
another anti-hypertensive drug in
terms of important clinical endpoints."
"Since the blood pressure reductions with
the two drugs were identical, then we
have to believe that blocking the
renin-angiotensin system […] is
critical in providing protection for
these vulnerable patients."
Heartbeat – May 2002
Weber
Triumph of the trials
LIFE: Discontinuations
Percentage
20
18
16
14
12
10
8
6
4
2
0
Atenolol
P<0.0001
Losartan
P<0.0001
P=0.006
Discontinuation due
to AE
Heartbeat – May 2002
Discontinuation due
to drug related AE
Discontinuation due
to serious drug
related AE
Dahlof et al. Lancet 2002;359:995-1003
Triumph of the trials
LIFE: Event rate
Losartan
14%
Atenolol
p=0.021
12%
10%
p=0.001
8%
6%
p=0.206
p=0.491
4%
2%
0%
Composite
Heartbeat – May 2002
MI
Stroke
Death
ACC 2002
Triumph of the trials
LIFE: Patient's view
"From a patient's point of view, these are
all major cardiovascular events and so
none of the three [death, MI, stroke]
is any good to have."
It is hoped this will provide guidance for
offering therapy a patient can comply
with easily
"This could be a terrific way to offer
appropriate blood pressure reduction."
Heartbeat – May 2002
Cannon
Triumph of the trials
LIFE: Combination therapy
It is hoped this will point toward research
into the effect of the renin-angiotensin
system on stroke
A patient with a prior MI should be on a
beta-blocker, and this suggests you
should add angiotensin II inhibition as
well
Cannon
Heartbeat – May 2002
Triumph of the trials
LIFE: HOPE results
Endpoint
ramipril
placebo
p value
Mortality
10.4%
12.2%
0.005
CV Death
6.1%
8.1%
<0.001
Stroke
3.3%
4.9%
<0.001
MI
9.9%
12.3%
<0.001
HOPE Investigators. N Engl J Med 2000; 342: 145-53
Heartbeat – May 2002
Triumph of the trials
LIFE: Differences with HOPE
HOPE compared ACE-inhibitor vs placebo
"The HOPE study was bedeviled by the
fact that there were blood-pressure
changes. Some people are even
arguing that much of the benefit of the
ACE inhibitor in HOPE could be
explained by the fact that it lowered
blood pressure pretty effectively."
Heartbeat – May 2002
Weber
Triumph of the trials
LIFE: New first-choice therapy
"You can make an argument right now
[…] that for any reasonably high-risk
hypertensive who came into your
office that an angiotensin-receptor
blocker might have to be your
number-one preferred drug to start
the treatment […] because it has gone
out and beaten the drug that is
currently recommended as the first
step in treatment."
Heartbeat – May 2002
Weber
Triumph of the trials
LIFE: Future trials
Antihypertensive Lipid Lowering Heart
Attack Trial – (ALLHAT)
doxazosin vs chlorthalidone
Valsartan Antihypertensive Long-term
Use Evaluation - (VALUE)
valsartan vs amlodipine
Heartbeat – May 2002
Triumph of the trials
LIFE: Matching blood pressure
"All these hundreds of millions of dollars
and years and years of effort will be
wasted, or at least greatly diluted, if
indeed we don't have equal blood
pressure effects so we can really look
at what goes beyond the blood
pressure."
Weber
Heartbeat – May 2002
Triumph of the trials
WIZARD: C pneumoniae in MI
4-5 years ago we believed that infections
are important in CVD
• C pneumoniae inside the arteries
• C pneumoniae inside the monocytes
• Small retrospective studies seemed to
support this idea
Heartbeat – May 2002
Fuster
Triumph of the trials
WIZARD: ACADEMIC
Azithromycin in Coronary Artery Disease:
Elimination of Myocardial Infection with
Chlamydia
302 patients with CAD and positive
serology for C pneumoniae randomized to
receive either placebo or azithromycin
No significant difference in primary
endpoint: CV death, non-fatal MI, or
unplanned revascularization
Circulation 2000; 102(15):1755-60
Heartbeat – May 2002
Triumph of the trials
WIZARD: CLARIFY
Clarithromycin in Acute Coronary
Syndrome Patients in Finland (CLARIFY)
148 patients randomized to placebo or
clarithromycin for 3 months
Patients were followed for up to 3 years
51% relative risk reduction in CV events
Circulation 2002; 105(13): 1555-60
Heartbeat – May 2002
Triumph of the trials
WIZARD: Infectious burden
German study links the number of
infections to severity of atherosclerosis
Circulation 2002; 105(1):15-21
"Where Framingham said risk factors are
important, now we are going to say the
number of infections are important but
you have to accumulate a number of them
to really have an impact."
Heartbeat – May 2002
Fuster
Triumph of the trials
WIZARD: Trial design
Weekly Intervention with Zithromax for
Atherosclerosis and its Related Disorders
7747 patients with were randomized to
12 weeks of either azithromycin or
placebo
Inclusion criteria
> 6 weeks post-MI
C pneumoniae 1:16
Heartbeat – May 2002
Triumph of the trials
WIZARD: Change in enrollment
WIZARD was originally powered to enroll
3000 patients and detect a 25%
difference
Pfizer got feedback saying that a 15-20%
event reduction would be acceptable, and
so expanded and extended the trial
"It was very courageous of a sponsor
because you don't see this often."
Heartbeat – May 2002
O'Connor
Triumph of the trials
WIZARD: Trial design
Primary composite endpoint:
Mortality
Reinfarction
Hospitalization for unstable angina
Revascularization
Trial concluded in Feb 2002 with >1000
adjudicated events
Heartbeat – May 2002
Triumph of the trials
WIZARD: Primary Endpoint
% of patients with event
30
Risk Reduction = 7%
95% CI = (-5, 17)
P-value = 0.23
25
20
15
Azith
Placebo
10
5
Time from Treatment Start (Months)
0
0
Heartbeat – May 2002
6
12
18
24
30
36
42
48
54
O'Connor – ACC2002
Triumph of the trials
WIZARD: Length of treatment
CLARIFY saw benefit appear after long treatment
and long follow-up, do you think we will see the
same with WIZARD?
When the study was planned, the issues around
duration of therapy were toxicology issues
A decision was made to go ahead and not wait for
the toxicology studies
O'Connor
Heartbeat – May 2002
Triumph of the trials
WIZARD:Treatment Effect by Time
Composite Endpoint
Death/MI
Censoring Time (years)
.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0
0.5
1
1.5
0
0.5
1
1.5
Hazard Ratio (95% CI)
Heartbeat – May 2002
O'Connor – ACC2002
Triumph of the trials
WIZARD: Duration is critical
"I think duration is critical, and therefore I
think there is still hope."
"You just have to treat this longer."
O'Connor
Heartbeat – May 2002
Triumph of the trials
WIZARD: PROVE-IT
PROVE-IT: Pravastatin or Atorvastatin
Evaluation and Infection Therapy
Patients will be randomized to pravastatin
or atorvastatin and to gatifloxacin or
placebo
Patients will receive gatifloxacin treatment
throughout the trial (minimum 18 months,
expected mean 24 months) for 10 days of
every month
Heartbeat – May 2002
Triumph of the trials
WIZARD: Toxicology
"Until we do have some sort of toxicology
data and some sort of sense of what
we're doing to our whole flora, I really
wouldn't know what to predict would
be the effect of giving an antibiotic for
that long and I would be very nervous
about that."
Weber
Heartbeat – May 2002
Triumph of the trials
WIZARD: Multiple infections
Are we too focused on one microorganism?
It could be like giving a statin to a
hypertensive patient or an antihypertensive to someone with high
cholesterol
Maybe there are multiple microorganisms
we need to target with different drugs
Heartbeat – May 2002
Fuster
Triumph of the trials
WIZARD: Multiple targets
We didn't make progress against
Hodgkin's disease until we began using
multiple agents
There is evidence for multiple organisms
in CVD
"It's tricky when you're talking about
duration of therapy."
Heartbeat – May 2002
O'Connor
Triumph of the trials
WIZARD: Use the drugs we have
"A lot of it is driven by what agents we
have. If we had an agent that could
effectively treat CMV without a lot of
toxicity that would certainly be worth
testing, but we just have easy
antibiotics that we used against
chlamydia."
Cannon
Heartbeat – May 2002
Triumph of the trials
WIZARD: Monitoring for superinfection
PROVE-IT is being monitored in a blinded
fashion
•previous trials found fewer infections
in the antibiotic groups
•multiple classes of agents allow us to
evade resistance
Both ACES and PROVE-IT should be out in
about 2 years
Cannon
Heartbeat – May 2002
Triumph of the trials
Summary: MADIT II
ICDs for post-MI patients
with low EF
Economic factors are
enormous
Should still do some kind of
EPS study to risk-stratify
patients
Heartbeat – May 2002
Triumph of the trials
Summary: Atrial fibrillation
We didn't get the quality of
life information we wanted
Mortality is not different
between rate or rhythm
control
Heartbeat – May 2002
Triumph of the trials
Summary: Coated stents
FIM study showed 0%
restenosis
RAVEL also shows 0%
restenosis in eluting-stent
arm
Heartbeat – May 2002
Triumph of the trials
Summary: DANAMI-2
Maybe it is time for patients
to be moved to PCI centers
Must have a system prepared
to use this
The economic impact of this
needs to be studied
Heartbeat – May 2002
Triumph of the trials
Summary: LIFE
Similar drop in blood
pressure with losartan but
significant benefits over
atenelol, especially in stroke
This may shift what we use
as first-line therapy in
hypertension
Heartbeat – May 2002
Triumph of the trials
Summary: WIZARD
We have much to learn about
the microorganisms affecting
the vascular system
WIZARD was disappointing,
showing no significant effect
of antibiotics
Heartbeat – May 2002
Triumph of the trials
Conclusions: O'Connor
It is exciting that we have the kinds of
studies that can change practice
"I think in particular DANAMI-2 and LIFE
will change the way I practice personally
and the way we recommend practices to
change in our healthcare system in North
Carolina."
Heartbeat – May 2002
O'Connor
Triumph of the trials
Conclusions: Weber
DANAMI-2
"There seems to be a different time clock for
the biology of what happens to a
thrombus and what happens to the
myocardium following an acute MI.
Clearly, after 4-6 hours its too late to do
anything about the thrombus, even so
apparently the myocardium may still be
very viable."
Heartbeat – May 2002
Weber
Triumph of the trials
LIFE: Patients with Diabetes
# of
Endpoint Events
Hazard Ratio (95% CI)
Composite 242
CV Death
99
Stroke 116
MI
91
Total Mortality 167
0.5
Heartbeat – May 2002
1
1.5
Favors L Favors A
L H Lindholm et al. Lancet 2002;359:1004-1010
Triumph of the trials
Conclusions: Weber
WIZARD
The presence of inflammatory markers does
not necessarily indicate infection
Angiotensin and aldosterone can stimulate
inflammatory reactions
Other mechanisms may be causing the rise
of inflammatory markers
Heartbeat – May 2002
Weber
Triumph of the trials
Conclusions: Cannon
To have so many good trials guiding therapy
is good for cardiology
"We all have lots of things we can change so
it keeps the field very fresh and good for
patients."
Heartbeat – May 2002
Cannon
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
Christopher M O'Connor MD
Associate Professor of Cardiology
Duke University Medical Center
Durham, NC
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Heartbeat – May 2002Brooklyn, New York