Giving tirofiban (Aggrastat, Medicure Pharma/Iroko Pharmaceuticals)
during elective PCI to patients who demonstrate aspirin and/or
clopidogrel resistance can significantly reduce the risk of
periprocedural MI, results from the 3T2R study suggest. According to
Dr Marco Valgimigli (University of Ferrara, Italy), who presented
the results during the September 2, 2008 hotline session at the
European Society of Cardiology Congress 2008, aspirin and/or
clopidogrel nonresponders who were given tirofiban during PCI nearly
halved their risk of MI, as compared with nonresponders given
placebo.

Importantly, Valgimigli noted, this reduction was seen without any
increase in bleeding. "If you look at all of the stories of
antithrombotics--bivalirudin vs GP IIb/IIIa inhibitors, prasugrel vs
clopidogrel--it's a very consistent message: if you do something to
improve either ischemia or bleeding, you increase the other side.
And in this study, I was a little bit surprised--we increased the
anti-ischemic effect, but we did not pay a price in terms of safety."

The study enrolled 263 patients who were nonresponders to either
aspirin or clopidogrel or both, based on the Accumetrics point-of-
care assay. All patients had silent ischemia or low-risk stable or
unstable coronary artery disease and were undergoing elective PCI.
They were randomized in a double-blind manner to receive tirofiban
(25 µg/kg in three minutes, followed by 12-24 hour infusion at 0.15
µg/kg/min) or placebo on top of standard aspirin and clopidogrel
therapy.

At 48 hours, the primary end point for the study--increase in
troponin I or T greater than three times the upper limit of normal--
was reduced by 42% in the tirofiban group, from 35.1% to 20.4%
(p=0.009). By 30 days, MACE rates were similarly reduced, driven
entirely by the reduction in periprocedural MI. No differences were
seen in major or minor bleeding between the placebo- and tirofiban-
treated patients.

More Proof Needed

"Our study provides proof of concept for a new treatment strategy in
patients with coronary artery disease, which, by assessing response
to standard antiplatelet agents by a point-of-care assay, modulates
intensity of treatment accordingly," Valgimigli concluded.

To heartwire, Valgimigli noted that another GP IIb/IIIa inhibitor
would likely produce similar results in aspirin/clopidogrel-
nonresponsive patients, although he and his coinvestigators chose
tirofiban because the bolus regimen they used "is the most powerful
platelet inhibitor on the market."

He also acknowledged what is likely the "major flaw" in his
study. "To make the proof of concept even sounder, we should have
also randomized those patients who were not poor responders to
aspirin or clopidogrel, to see whether the ischemic end point was
not there. But we focused on a very low-risk patient population
based on clinic characteristics, and nobody has ever shown that a GP
IIb/IIIa inhibitor is effective in this population [on top of]
aspirin and clopidogrel."

Indeed, commenting on the results for heartwire, Dr John Alexander
(Duke University Medical Center, Durham, NC) called the phenomenon
of aspirin and clopidogrel variable responsiveness "complicated."

"We know that a patient population that has less responsiveness to
aspirin and/or clopidogrel is more likely to have recurrent ischemic
events, and it's not particularly surprising that tirofiban benefits
them," he said. "The key thing that is missing in this study is what
happens if you give tirofiban to the patients who are not aspirin or
clopidogrel nonresponsive. The primary effects of the GP IIb/IIIa
inhibitor are to reduce periprocedural MI, and that's exactly what
we saw here."

Dr Freek W A Verheugt (Radboud University Nijmegen Medical Centre,
the Netherlands), who discussed the trial following its presentation
in the hotline session, also zeroed in on the lack of an
aspirin/clopidogrel-responsive control.

Verheugt pointed out that tirofiban has a 12-year history as an
effective antiplatelet agent on top of aspirin and is already part
of the European guidelines for PCI.

"There's nothing new here," he said. "Although this study was very
well done, it will not change current guidelines or current
practice," he suggested. Future studies will have to test the
effects of GP IIb/IIIa inhibition in both aspirin- and clopidogrel-
responsive and -nonresponsive patients before a strategy of testing
for antiplatelet nonresponsiveness pre-PCI can be justified, he
concluded.

Valgimigli disclosed being on the speaker's bureau for Merck,
Medicure, and Iroko; receiving research grants from Merck, Iroko,
and Eli Lilly; and being on the advisory board for Iroko, Eli Lilly,
and the Medicines Company.