Transcript OPTIMAAL - Medscape

OPTIMAAL
OPTIMAAL: Does the dose make
the medicine?
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
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OPTIMAAL
ACE inhibitor vs ARB
Patients with complicated acute MI
with heart failure or significant
systolic dysfunction are at high risk
OPTIMAAL pitted an angiotensin
receptor blocker (losartan) vs
standard ACE inhibitor (captopril) in
these patients
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Califf
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.
• Primary end point: all-cause mortality
at 2.7 years' follow-up.
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OPTIMAAL
Results
Rate of end point (%)
captopril
20
18
16
14
12
10
8
6
4
2
0
p=0.069
p=0.722
Mortality
MI
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losartan
p=0.032
CV death
p=0.587
Stroke
Lancet 360:752-760
OPTIMAAL
Head-to-head trial
Give credit to Merck for doing a
head-to-head trial
"We always learn a lot from these
trials, even though in the old
days people called them 'not
creative,' 'boring,' terms like
that."
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Califf
OPTIMAAL
Titration phase
Separation of the mortality curves
all occurs in the first month, during
the titration phase
After the first month, the curves are
the same except for the
discontinuation
losartan -- 17%
captopril -- 23%
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Califf
OPTIMAAL
Mortality with losartan
Mortality (%)
comparitor
20
18
16
14
12
10
8
6
4
2
0
p=0.069
OPTIMAAL
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losartan
p=0.016
ELITE-2
p=0.206
LIFE
OPTIMAAL
Questions
Is that early remodeling phase very
important in terms of reninangiotensin system inhibition?
Is it just a dosing issue?
"If you get the wrong dose, maybe
the drug is not going to be as
good."
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Califf
OPTIMAAL
Importance of dosing
You shouldn't start a big trial until
you know what the ideal dose is
"This study would suggest that ACE
inhibition is still the anchor
therapy."
Need to piece together clues from
many trials
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Topol
OPTIMAAL
LIFE: Primary composite end point
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
12
4460
4414
18
4392
4349
24
4312
4289
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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
OPTIMAAL
Changing the wrong dose
"I think sometimes we end up with the wrong
dose just because it's too much trouble to go
through all the decisions to get it changed."
Califf
"That's unfortunate, really. When you put
thousands of patients through an experiment,
you would hope that you're giving it your best
shot."
Topol
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OPTIMAAL
TARGET dosing
No one knows if the dosing in TARGET
was incorrect, even if that is a possible,
plausible explanation of the results
Tirofiban: 10µg/kg bolus, 0.15 µg/kg per
min infusion (18- to 24-hr duration)
Abciximab: 0.25 µg/kg bolus, 0.125
µg/kg per min infusion to maximum 10
µg/min (12-hr duration)
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OPTIMAAL
Multiple dose trials
It can be months to get anything
changed in a protocol with major
trials
"I'm afraid that my view is the only
way to deal with this is to do large
trials with several doses. . . . But
we'd just run up against the
practical difficulty of sample size
and what it takes to get there."
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Califf
OPTIMAAL
Future trials
Future trials should tell us a lot about
dose for ARB vs ACE inhibitors:
VALIANT
(valsartan in acute myocardial infarction)
CHARM
(candesartan in heart failure assessment
of reduction in mortality)
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