New Pharmacodynamic Data Confirm PLATO Genetics Substudy Findings

November 16, 2010

November 15, 2010 (Chicago, Illinois) Ticagrelor (Brilinta, AstraZeneca) is better at inhibiting platelet function than clopidogrel independent of CYP2C19 genotype or metabolizer status, new data show [1]. The findings were published today in Circulation Cardiovascular Genetics by Dr Udaya S Tantry (Sinai Center for Thrombosis Research, Baltimore, MD) and colleagues and presented simultaneously at the American Heart Association 2010 Scientific Sessions by senior author Dr Paul A Gurbel (Sinai Center for Thrombosis Research).

This is the first study to look at the effect of genotype on pharmacodynamics in patients treated with ticagrelor, Gurbel told heartwire . Although these results "could have been anticipated, from indirect comparisons," says Gurbel, "it was never known, for example, whether clopidogrel had equivalent antiplatelet effects to ticagrelor."

You may obviate the need for platelet-function testing if you chose ticagrelor, because patients are having a uniform antiplatelet effect.

These findings confirm the previous outcomes results of the PLATO pharmacogenetics substudy reported in the summer, he says. "Our data match nicely with the PLATO genetics study, which says that no matter what your genotype is, you're better on ticagrelor than clopidogrel. Our data say no matter what genotype, your pharmacodynamic effect is better on ticagrelor than clopidogrel."

The clinical implications of these findings are that on-treatment platelet reactivity "will always be lower on ticagrelor than on clopidogrel, irrespective of genotype," says Gurbel, and "if you want a predictable response, you would chose ticagrelor rather than clopidogrel. You may obviate the need for platelet-function testing if you chose ticagrelor, because patients are having a uniform antiplatelet effect compared with a variable antiplatelet effect with clopidogrel."

The new findings come from ONSET/OFFSET and RESPOND, which were two phase 2 trials designed to assess the onset and offset of platelet inhibition of ticagrelor (180-mg loading dose plus 90-mg twice-daily maintenance dose) vs clopidogrel (600-mg loading dose plus 75-mg daily maintenance dose); the effects of ticagrelor in patients not responding to clopidogrel; and the effect of switching patients between clopidogrel and ticagrelor. Gurbel said the analysis could not determine the effects of ticagrelor relative to those of a 150-mg daily maintenance dose of clopidogrel, as this was not examined in the trials.

CYP2C19 genotyping was performed in both sets of patients. Platelet function was measured ex vivo by aggregometry, the VerifyNow assay (Accumetrics, San Diego, CA) and the vasodilator-stimulated phosphoprotein (VASP) assay at baseline, at eight hours postloading and during maintenance. In each treatment group, patients were categorized according to 2C19-genotype carrier status (loss-of-function, gain-of-function) and metabolizer status. Platelet function was compared among these categories within each treatment group and also between the clopidogrel and ticagrelor groups for each category.

Patients receiving ticagrelor exhibited lower platelet reactivity than clopidogrel by all assays--irrespective of 2C19 genotype or metabolizer status (p<0.01). Loss-of-function carriers had greater platelet reactivity during clopidogrel therapy. The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow assay.

Still a Role for Clopidogrel, Says Editorialist

In an accompanying editorial [2], Dr Amber L Beitelshees (University of Maryland, Baltimore) discusses what is known about the pharmacology of ticagrelor that explains these findings and the previous ones from the PLATO genetics substudy. She notes that ticagrelor is not metabolized by CYP450 enzymes, so it is not prone to common drug interactions or influenced by genetic polymorphisms, as is the case for clopidogrel. Other reasons that might account for the better outcomes with ticagrelor over clopidogrel are that the former has a faster onset of action than the latter and provides more complete inhibition of the P2Y12 receptor, she says.

In patients in whom adherence is an issue, clopidogrel or prasugrel may be more appropriate choices, given the requirement for twice-daily dosing.

But she cautions, "The world of personalized antiplatelet therapy for patients with CAD is still very much in flux. Clopidogrel will be coming off patent soon, so cost will be a factor for payers in determining which antiplatelet therapies to cover. Ticagrelor has yet to obtain FDA approval, and further, in patients in whom adherence is an issue, clopidogrel or prasugrel may be more appropriate choices given the shorter duration of action of ticagrelor and hence, requirement for twice-daily dosing." Other factors to take into consideration are adverse effects with ticagrelor such as dyspnea and indications for which it has not yet been studied, including stroke and peripheral arterial disease, she says.

"Taken together, there likely will be patients in whom clopidogrel remains indicated and in whom it will be useful to understand factors associated with and method for overcoming nonresponse," she concludes.

The study was funded by AstraZeneca. Wei and another coauthor are employees of AstraZeneca. Gurbel receives research grants, honoraria and consultant fees from Haemascope, AstraZeneca, Schering-Plough/Merck, Medtronic, Lilly/Sankyo, Sanofi-Aventis/Bristol-Myers Squibb, Portola, Boston-Scientific, and Bayer. Beitelshees has no conflicts.

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