BRAVO and oral GP IIb/IIIa

Clinical Trial Commentary

Dr Eric TopolChairman and Professor, Department of CardiologyDirector of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Why BRAVO was stoppedBRAVO

Adverse events at safety review (n=9200)

Outcome Lotrafiban % Placebo % p-value

Mortality 2.7 2.0 0.022

Thrombocytopenia 2.2 0.5

Major bleeding 4.2 1.3 <0.0001

Meta-analysis of oral IIb/IIIa trials

EXCITE

OPUS

SYMPHONY

Pooled

1.0%

1.4%

1.8%

1.4%

1.35%

1.95%

2.00%

1.80%

Death

Odds Ratio & 95% CITrial Placebo Fiban

Placebo BetterFiban Better

7,232

10,302

9,169

26,703

N

p = 0.616 Breslow-Day

homogeneity

0 0.5 1 1.5 2

Xemilofiban

Orbofiban

Sibrafiban

p = 0.023

1.36

1.40

1.12

1.27

BRAVO

What is the cause?

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.

BRAVO

Partial agonist effect

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.

BRAVO

Thrombotic pathWhat 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)

BRAVO

Inflammatory path

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.

BRAVO

Apoptosis

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?

BRAVO

Questions raised

1) 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?

BRAVO

PLA polymorphism

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

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% increase in 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 CardiologyDirector of the Joseph J Jacobs Center for Thrombosis and

Vascular Biology at the Cleveland Clinic

BRAVO

Oral GP IIb/IIIa inhibitors

What is a class?

How do you define a class or a class effect?

Along what characteristics do you divide up the agents?

Are there any exceptions?

BRAVO

What we have learned

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.

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

BRAVO

Diabetes

Class

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

BRAVO