Dr Franck Paganelli

Others, however, point out that cardiologists have not yet agreed what test is the best in terms of measuring how well patients are responding to antiplatelet therapy or on the best strategy for acting on any information gleaned.

Paganelli et al screened 1122 patients undergoing nonemergent PCI for clopidogrel responsiveness, after they'd received their 600-mg loading dose (plus 250-mg aspirin). Responsiveness was defined by a vasodilator-associated stimulated phosphoprotein (VASP) index of 50% or greater, based on a test that measures the extent to which clopidogrel binds, in vivo, to the P2Y₁₂ platelet-surface chemoreceptor. In all, 429 patients deemed to have reduced responsiveness were ultimately randomized to the control group, receiving a maintenance dose of clopidogrel (75 mg), or to a VASP-guided loading dose of up to three additional loading doses of 600 mg every 24 hours until VASP was reduced below 50% pre-PCI.

Thirty-day definite stent thrombosis postprocedure—the primary end point of the study—was significantly reduced in patients in the VASP-guided group as compared with controls, with almost all stent thromboses occurring in the first seven days. There were statistically nonsignificant trends toward reduced cardiovascular death and reduced repeat revascularizations and a significantly reduced risk of MI in the VASP-guided group. Overall MACE was, as a result, significantly lower in the VASP-guided arm of the study. There were no differences in bleeding rates in the VASP-guided group

"The first message from this study is that an adjusted loading dose of clopidogrel according to platelet-responsiveness monitoring decreases the rate of stent thrombosis at 30 days in patients with clopidogrel low response, without increasing bleeding," Paganelli concluded.

The second point, he continued, is that patients can be thought of as falling into one of three groups—good responders, low responders, and resistant patients, whose loading dose of clopidogrel may need to be tweaked prior to PCI.

And last, he said, borrowing from the rallying cry of US President-elect Barack Obama's campaign, "The third message is: Yes we can! Yes, we can now [identify] the therapeutic window for antiplatelet therapy in patients undergoing PCI to avoid MACE. It's a new paradigm."

Dr Elliot Antman

Dr Elliot Antman (Brigham and Women's Hospital, Boston, MA), discussing the results, congratulated the authors for their pioneering work in this field but highlighted the need for further studies to clarify the logistics, accuracy, and replicability of platelet-responsiveness tests as well as the appropriate action to take.

For starters, said Antman, the VASP index is "a rather specific test" for measuring clopidogrel responsiveness. "We could discuss whether 50% is the ideal cutoff, and I would suggest to you that we are still learning how to use these antiplatelet tests; I personally believe we are not as confident about the antiplatelet-responsiveness tests as we are about INR with respect to the target," he commented in a press conference.

The procedure described by Paganelli also entails "iterative loading doses" that require time for the drug dose to exhibit an effect, then more time for the lab result to come back.

During the late-breaking clinical-trial presentation, Paganelli clarified that he and his colleagues have already adjusted their practice to avoid long delays. Regardless of the VASP test, he says, patients proceed to PCI but then are sent home, and if their VASP results come back higher than 50%, their maintenance dose is upped at home.

Antman, however, says more evidence is needed to justify a strategy of altering drug dosages on the basis of responsiveness tests, particularly since there is no widespread consensus as to what test should be used. "We need more information about the integrity of these laboratory tests and how we should use them," he said. A laboratory test, he argues, should correlate well with outcomes, capture therapy effect completely, and be reproducible across other therapies in the class of drug. The GRAVITAS trial, he noted, will provide further information in this regard.

But Antman also suggested that there are different ways to deal with the variation in clopidogrel response, the first being a strategy of "empirically" giving a higher dose. That strategy is the subject of the ongoing OASIS 7 trial, he noted.

Finally, Antman pointed out newer therapies still in the pipeline may provide more consistent antiplatelet action, including prasugrel, believed by many to be poised for FDA approval, and newer drugs such as AZD6140 and the intravenous agent cangrelor.