Thumbs up/Thumbs down – Oct 2002 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

Thumbs up/Thumbs down – Oct 2002 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 Califf

Thumbs up/Thumbs down – Oct 2002 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.

Thumbs up/Thumbs down – Oct 2002 OPTIMAAL Lancet 360: Results p=0.069p=0.032p=0.722p=0.587

Thumbs up/Thumbs down – Oct 2002 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." Califf

Thumbs up/Thumbs down – Oct 2002 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% Califf

Thumbs up/Thumbs down – Oct 2002 OPTIMAAL Mortality with losartan p=0.069p=0.016p=0.206

Thumbs up/Thumbs down – Oct 2002 OPTIMAAL 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

Thumbs up/Thumbs down – Oct 2002 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 Topol

Thumbs up/Thumbs down – Oct 2002 OPTIMAAL LIFE: Primary composite end point 6 Proportion of patients with first event (%) Losartan Atenolol Dahlof et al. Lancet 2002;359: Intention-to-treat 12 Adjusted risk reduction 13.0%, p=0.021 Unadjusted risk reduction 14.6%, p=0.009 Study Month Losartan (n) Atenolol (n)

Thumbs up/Thumbs down – Oct 2002 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

Thumbs up/Thumbs down – Oct 2002 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, µg/kg per min infusion to maximum 10 µg/min (12-hr duration)

Thumbs up/Thumbs down – Oct 2002 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." Califf

Thumbs up/Thumbs down – Oct 2002 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)