TRILOGY/ARCTIC: Back to the Drawing Board for Platelet Monitoring

November 04, 2012

LOS ANGELES — The role of platelet-function monitoring has suffered another serious setback, with two new studies adding to several others that suggest no benefit of such an approach.

The TRILOGY ACS substudy found no independent association of platelet function and ischemic outcomes in medically managed ACS patients [1]. Meanwhile, the ARCTIC trial found no benefit of platelet-function testing and modification of treatment in patients receiving drug-eluting stents [2].

The studies were presented here today at the American Heart Association 2012 Scientific Sessions. They are also published online, ARCTIC in the New England Journal of Medicine and the TRILOGY substudy in the Journal of the American Medical Association (JAMA).

TRILOGY Substudy

The results of the main TRILOGY trial, reported at the European Society of Cardiology 2012 Congress in August, showed no difference in clinical outcomes with prasugrel (Effient, Lilly/Daiichi-Sanyo) vs clopidogrel in patients with medically managed unstable angina or non-ST-segment elevation MI. Of 9326 patients in the main trial, 27% were included in the platelet-function substudy. Results showed that although prasugrel was associated with lower platelet reactivity than clopidogrel and there was a relationship between platelet reactivity and occurrence of ischemic outcomes, this was no longer present after adjustment for other risk factors.

Lead author Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD) told heartwire that the platelet substudy explains the results of the main TRILOGY trial. "In the substudy, there was no independent relation of platelet reactivity to outcome occurrence and, in the main trial, more potent platelet inhibition did not reduce event frequency. These findings suggest that the P2Y12 pathway is not a major player driving ischemic event occurrence in medically managed ACS patients. In summary, I would not use platelet-function testing to guide therapy in medically managed ACS patients based on the TRILOGY findings."

In a JAMA editorial accompanying the TRILOGY substudy publication, Dr Matthew Price (Scripps Clinic, La Jolla, CA) reminds that P2Y12-mediated platelet reactivity has been linked to adverse outcomes many times in PCI patients, although it appears to be less pronounced in stable patients [3].

ARCTIC: Platelet Testing Left Cold

The ARCTIC trial, however, still found no benefit of platelet-function testing in 2440 patients receiving drug-eluting stents (70% elective, 30% ACS). It differed from the TRILOGY substudy in that ARCTIC was actually a randomized study specifically looking at monitoring platelet function (with the VerifyNow test) and adjusting antiplatelet therapy accordingly vs no monitoring and conventional clopidogrel therapy.

Patients in the monitored group received platelet-function tests for both aspirin and P2Y12 inhibitors before angiography and again two to four weeks after stent implantation. Results showed that 34.5% of patients taking clopidogrel had high platelet reactivity before PCI. Of these, 80% received an additional clopidogrel loading dose. An additional loading dose of prasugrel was given to 3% of patients. In addition, the monitored group was much more likely to receive a GP IIb/IIIa blocker. High platelet reactivity in response to aspirin was rare before stent implantation and led to an additional bolus of IV aspirin in four of five patients.

In the monitoring group at the time of discharge, 9.3% of patients were being treated with prasugrel, half of those on clopidogrel were receiving a maintenance dose of 150 mg or more, and 37% were receiving a dose of aspirin of over 100 mg.

Measurement of platelet reactivity two to four weeks later showed that just 15% of patients had a poor response to clopidogrel; these patients were switched to prasugrel or had the clopidogrel dose increased by 75 mg. Despite this, the monitoring group did not have a lower event rate than the conventional group.

ARCTIC: Major End Points at One Year

End point Monitoring (%) Conventional (%) HR (95% CI) p
Death/MI/ stent thrombosis/stroke/urgent revascularizationa 34.6 31.1 1.13 (0.98–1.29) 0.10
Stent thrombosis/urgent revascularizationb 4.9 4.6 1.06 (0.74–1.52) 0.77
Major bleeding 2.3 3.3 0.70 (0.43–1.14) 0.15

a. Primary end point

b. Main secondary end point

The ARCTIC researchers conclude: "These data do not support the routine use of platelet-function testing in patients undergoing coronary stenting."

Dr Gilles Montalescot (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), senior author, commented to heartwire : "ARCTIC was the next step after GRAVITAS, which showed no benefit of doubling the clopidogrel dose in patients with high platelet activity. We allowed a broader range of options, including increasing clopidogrel, switching to prasugrel, and, on top of that, adding IIb/IIIa blockers, which were taken by 80% of patients found to have high platelet reactivity--but still we found absolutely no hint of benefit."

Montalescot concludes: "While platelet activity does appear to correlate with risk, it does not appear to be a modifiable risk factor and therefore should not guide treatment. It does not appear that personalized medicine is the way to go in this field. At present, measuring platelet function has a class IIb recommendation. But now, with this data, I don't think it will be recommended at all."

The lead author of ARCTIC, Dr Jean-Philippe Collet (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), added: "Platelet reactivity is very much more complex than we originally thought. I would say measuring platelet function still has a role in certain situations, such as if there is a major bleed or stent thrombosis, but this study shows that there is no role for using this one test to guide treatment for all patients."

Combination of Tests May Be Better?

But Collet is refusing to give up on the field altogether. He is now interested in focusing on using a combination of platelet tests to further define a high-risk population. He commented to heartwire : "The problem with these tests is that they have a poor predictive value individually. But there are many tests, which all measure different things. Maybe if we combine these tests along with genetic tests we can identify a group of patients who will benefit from intensification of therapy."

Senior TRILOGY investigator Dr Magnus Ohman (Duke Clinical Research Institute, Durham, NC) agrees with Collet. He commented: "The TRILOGY substudy tells us that this single marker measuring ADP-mediated platelet activation is not giving us the whole picture. It is more complicated than that. There are six or seven different receptors on platelets, and we have just measured one." And while TRILOGY was in medically managed ACS patients, Ohman pointed out that all the studies of platelet monitoring in PCI patients have also been negative. "But this may be due more to methodology than biology," he suggested.

Specifically on the ARCTIC study, he added: "I don't think this means that monitoring is not a viable strategy in selected patients, but we may need to do much more work to understand what affects platelet reactivity that is driven by common clinical characteristics."