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Text sizeCleveland, OH - The Blockade of the IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial, showing an increase in mortality with the oral GP IIb/IIIa blocker lotrafiban in patients with vascular disease, published online July 21, 2003 as a rapid track publication in Circulation.1
The trial was stopped prematurely in December 2000 when the negative effect of lotrafiban on mortality became apparent. Lotrafiban, which has now been discontinued, was the fourth oral IIb/IIIa blocker to show an adverse outcome in clinical trials, joining orbofiban, xemilofiban, and sibrafiban, all of which had already been dropped from development when BRAVO was stopped.
A few other oral IIb/IIIa blockers with different pharmacokinetic profiles remained in development after the lotrafiban failure, but these are also now believed to have been dropped, bringing the entire field of investigation to an end.
In the BRAVO trial, patients with vascular disease were randomized to lotrafiban or placebo in addition to aspirin, with a two-year follow-up. The primary end point was the composite of all-cause mortality, MI, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries, 41% had cerebrovascular disease at the time of entry and 59% had coronary artery disease.
Death occurred in 2.3% of the placebo patients and 3.0% of lotrafiban patients (hazard ratio 1.33, p=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% placebo vs 16.4% lotrafiban [HR 0.94]). Serious bleeding was more frequent in the lotrafiban group (8.0% vs 2.8%; p=0.001) and among those who received higher doses of aspirin (above 162 mg/day) with or without lotrafiban.
In the Circulation paper, the BRAVO investigators, led by Dr Eric Topol (Cleveland Clinic, OH), say the trial is noteworthy for three major findings:
It confirms the increased risk of fatality and serious bleeding for oral IIb/IIIa inhibition.
It demonstrates for the first time that the increased risk of fatality is also extended to patients with cerebrovascular disease.
It suggested that doses of aspirin higher than 162 mg/day were associated with an increased risk of the primary composite end point and an increased risk of serious bleeding and transfusion.
Aspirin dose may be most important finding
Topol commented to heartwire that the observations on aspirin dose may be the most important finding of the BRAVO trial, since prior work in the field has been hard to sort out. "Doses of less than 162 mg were much safer. There is an unequivocal doubling of major bleeding going from 81 mg to 325 mg, and we have a lot of work to do to lower the dose of aspirin based on BRAVO, CURE, and other recent trials," he added.
Doses of less than 162 mg were much safer. There is an unequivocal doubling of major bleeding going from 81 mg to 325 mg, and we have a lot of work to do to lower the dose of aspirin.
In the Circulation paper, the researchers note that although the dose of aspirin used in BRAVO was nonrandomized and was left to individual physician-investigators to decide, there was a very large population with a considerable number of events during extended follow-up. Although the assessment of aspirin dosing will require further intensive analysis from the BRAVO database, there was strong evidence for heightened risk of serious bleeding with doses higher than 162 mg per day, they write. They add, however, that the current trial did not collect information concerning aspirin dose during extended follow-up, because only the dose used at study entry was available, emphasizing the need for more dedicated clinical research to determine the optimum dose of aspirin.
They conclude: "It appears that doses of aspirin less than 162 mg/day may be prudent to avoid bleeding complications for the time being, unless patients are at particularly high risk, in which case, consideration of a dose of 325 mg/day may be appropriate but will be associated with increased bleeding complications. Without question, further assessment of aspirin dosing through large-scale, randomized trial investigations would be helpful to clarify optimal antiplatelet therapy for patients with atherosclerotic vascular disease."
One third increase in mortality with lotrafiban
The authors note that the 33% increase in mortality seen with lotrafiban in this study is in keeping with that seen in previous trials of other oral IIb/IIIa blockerswhich together showed a 37% excess in fatality rate. They report that this higher risk of fatality appeared to be increasing over the duration of drug exposure and was largely attributable to an excess of vascular deaths. Although attempts were made in the present trial to titrate the dose of lotrafiban according to the patient's age and calculated creatinine clearance, this did not achieve any reduction of risk.
Although noting that the precise mechanism is not known for the increased risk of death due to oral IIb/IIIa inhibition, they suggest that these agents may not completely block the IIb/IIIa receptor and this could bring shedding of platelet CD40 ligand, which has both prothrombotic and proinflammatory roles.
The BRAVO authors finish by addressing the issue of whether the trial was ethical, given the negative data from previous studies of similar agents. In justifying the trial, they say that: "The present trial was initiated before the results of SYMPHONY I and II and the meta-analysis of previous trials were available. Previous assessment of risk in the orbofiban trial had suggested that titrating the dose for renal impairment would reduce the risk of adverse events, and this was a major strategy incorporated in the lotrafiban project. Careful surveillance of risk was monitored during the trial by an experienced data and safety monitoring board, and the first time there was a significant demonstration of hazard, the trial was stopped. Consideration was given to stopping the trial before this point on the basis of the results of other trials, but the lack of evidence of hazard, the unique population under study, and the specific dose and drug strategy led to continuation with close monitoring."
No PURPOSE for roxifiban either
One of the other oral IIb/IIIa blockers that was still in development at the time BRAVO was stoppedroxifibanhas also shown disappointing results and is believed to be no longer in development. Roxifiban showed much tighter binding to the IIb/IIIa receptor than the other oral IIb/IIIa blockers, and it was hoped for this reason that it might not be associated with the same problems. It was tested in a different patient populationwith peripheral artery diseasein the PURPOSE trial.
One of the investigators in this trial, Dr Chris Cannon (Brigham & Women's Hospital, Boston, MA) told heartwire that a very high level of steady inhibition was achieved, which would in theory be good for efficacy, but there was a fivefold increase in major bleeding, leading to the trial being stopped after just 300 patients had been enrolled. "With the benefits seen with clopidogrel, I think the oral IIb/IIIa inhibitors are dead," Cannon added.
