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Clinical Trial Commentary

Clinical Trial Commentary. BRAVO and oral GP IIb/IIIa. Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for

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Clinical Trial Commentary

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  1. Clinical Trial Commentary BRAVO and oral GP IIb/IIIa Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

  2. Why BRAVO was stopped BRAVO

  3. Meta-analysis of oral IIb/IIIa trials BRAVO Death N Odds Ratio & 95% CI Fiban Placebo Trial 1.36 EXCITE 1.35% 1.0% 7,232 Xemilofiban 10,302 1.40 OPUS 1.95% 1.4% Orbofiban 1.12 9,169 SYMPHONY 2.00% 1.8% Sibrafiban 1.80% 1.4% 1.27 p = 0.023 26,703 Pooled 0 0.5 1 1.5 2 p = 0.616 Breslow-Day homogeneity Fiban Better Placebo Better

  4. What is the cause? BRAVO • 3 leading explanations • Partial agonist effect: • Less than 80% blockade, resulting in activation and a pro-thrombotic effect. • Inflammatory process: • Sub-threshold receptor blockade could release CD-40 ligand and selectin, provoking inflammation. • Apoptosis: • Direct inducement of cardiomyocyte apoptosis, causing arrhythmias.

  5. Partial agonist effect BRAVO • Can’t reach 80% blockade with oral therapy because of bleeding complications. • Oral GP IIb/IIIa inhibition is left at 30-50% blockade. • Intravenous administration has been able to reach 80-90% in short-term, acute use. • This sub-threshold level results in platelet activation.

  6. Thrombotic path BRAVO • What is activated? • Prothrombin complex is activated. • (But no corresponding increase of thrombotic events has been shown) • P-selectin is activated. • (adhesion receptor on platelet surface) • The thrombosis supposition is suspect. • (Many negative papers studying this effect have not yet been published)

  7. Inflammatory path BRAVO • CD-40 ligand shedding caused by sub-threshold receptor blockade • CD-40 is a pro-inflammatory mediator, stimulates white cells, and could also be involved in a thrombotic pathway • Studies presented at AHA 2000 are not yet published.

  8. Apoptosis BRAVO • Fitzgerald found that GP IIb/IIIa inhibitors can provoke cell death in rat cardiomyocytes. • Effect was dose dependent, which doesn’t fit with the partial agonist idea. • If this was the operative mechanism, why did it take a year for the deaths to show up in the BRAVO trial?

  9. Questions raised BRAVO • What does this mean for the one ongoing trial? • 2) What does this mean for the intravenous IIb/IIIa inhibitors? • 3) Does this mean anything for the other so-called antiplatelet drugs? What is a class?

  10. PLA polymorphism BRAVO • Desmond Fitzgerald has suggested that the OPUS trial saw outcomes dependent on PLA polymorphism • PLA-2 is present in 20%-25% of patients and is already associated with worse outcomes • Data on any interaction not yet in print

  11. Oral GP IIb/IIIa inhibitors BRAVO • “I've never been more convinced of a bad drug class than this. Because this is so intensively studied. But I think it would be obviously only with the oral IIb/IIIa. […] but this class kind of reeks of badness from the biology, and obviously worse than that, much worse than that, is the consistent death risk of 35% increasein death in 43 000 patients, 4 agents, 5 trials. I don't know how much more convincing one would need.” • Dr Eric Topol • Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

  12. What is a class? BRAVO • How do you define a class or a class effect? • Along what characteristics do you divide up the agents? • Are there any exceptions?

  13. What we have learned BRAVO • Even with extreme caution, it is very difficult to stop a trial in time to prevent increased mortality. • Phase II trials can be very misleading, and give strong misimpressions.

  14. Diabetes BRAVO • “I don't think treating diabetes is not a realm for cardiologists. I think obviously it's critically interrelated […] To me one of the instructive things about the development and problems of this class of drugs is that in phase III studies were done capable of detecting differences in mortality that are way below the threshold that most therapies today that are chronically given to people with a variety of diseases could even come close to picking up.” • Dr Robert Califf • Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

  15. Class BRAVO • Classes are an easy point of reference for guidelines • Talking about individual drugs often gets contentious • Must be very careful before assigning things to a “class” and assuming they all act alike

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