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OPTIMAAL: Does the dose make the medicine?

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

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OPTIMAAL: Does the dose make the medicine?

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  1. OPTIMAAL: Does the dose make the medicine? Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

  2. 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.

  4. Results p=0.069 p=0.722 p=0.032 p=0.587 Lancet 360:752-760

  5. 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

  7. Mortality with losartan p=0.069 p=0.016 p=0.206

  8. 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

  9. 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%, p=0.021 Unadjusted risk reduction 14.6%, p=0.009 2 0 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 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 2002;359:995-1003

  11. 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

  12. 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)

  13. 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

  14. 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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