OPTIMAAL: Does the dose make the medicine?

1
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 Clevela
  nd, 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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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

Califf
3
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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Results
p0.069
p0.032
p0.722
p0.587
Lancet 360752-760
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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."

Califf
6
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

Califf
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Mortality with losartan
p0.069
p0.016
p0.206
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Questions

• Is that early remodeling phase very important in
  terms of renin-angiotensin system inhibition?
• Is it just a dosing issue?
• "If you get the wrong dose, maybe the drug is
  not going to be as good."

Califf
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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
  

Topol
10
LIFE Primary composite end point
16
Intention-to-treat
14
Atenolol
12
Losartan
10
8
Proportion of patients with first event ()
6
4
Adjusted risk reduction 13.0, p0.021 Unadjusted
risk reduction 14.6, p0.009
2
0
6
18
24
30
36
42
48
54
60
66
0
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Study Month
Losartan (n)
4605
4524
4460
4392
4312
4247
4189
4112
4047
3897
1889
901
Atenolol (n)
4588
4494
4414
4349
4289
4205
4135
4066
3992
3821
1854
876
Dahlof et al. Lancet 2002359995-1003
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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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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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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."

Califf
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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)