ANTARCTIC: Platelet Monitoring No Benefit in Elderly ACS

August 28, 2016

ROME, ITALY — Monitoring platelet function and individualizing antiplatelet therapy did not improve outcomes for elderly ACS patients undergoing coronary stenting, results of the ANTARCTIC trial show[1].

The trial—presented today at the European Society of Cardiology (ESC) 2016 Congress and simultaneously published online in the Lancet—challenge current international guidelines, which recommend platelet-function testing in high-risk patients.

Senior investigator Dr Gilles Montalescot (Hôpital Pitié-Salpêtrière, Paris, France) commented: "Measuring platelet function is a complex and costly procedure and does not appear to benefit patients, even when they present with extremely high risk of ischemic and bleeding events liked those enrolled in ANTARCTIC."

Dr Gilles_Montalescot

The trial was conducted after a similar study—ARCTIC—showed no benefit of platelet-function testing and treatment modification in a lower-risk population—stable patients undergoing elective stenting. "There were some concerns that the low-risk population in ARCTIC may not have had enough events to be able to show a difference, and the antiplatelet therapy used was predominantly clopidogrel. We thought we might be able to show a benefit in a higher-risk population and by using prasugrel [Effient, Lilly/Daiichi Sankyo]—a more potent antiplatelet agent—in those with more platelet reactivity. This is what we tested in ANTARCTIC, but we still didn't find any difference in event rates or bleeding," Montalescot said.

"ANTARCTIC confirms the ARCTIC study in a different population with a different drug and has addressed the potential limitations of the ARCTIC study but finally reached the same conclusion. I expect there will be adjustments of guidelines and practice in light of this," he concluded.

In the Lancet paper, the ANTARCTIC authors write, "European and American guidelines do not recommend the routine use of platelet-function tests before or after stenting (class III, level of evidence A); however, a class IIb recommendation with level-C evidence is given for potentially high-risk situations, including suspicion of resistance to treatment or high bleeding risk. We believe that our study does not support this recommendation. A class IIa recommendation with level C evidence was issued for platelet-function monitoring to guide antiplatelet interruption before coronary arterial bypass graft surgery. This recommendation would also deserve a specific randomized study."

Commenting on the results, chair of an ESC press conference at which the study was discussed, Dr Stephan Gielen (Detmold Hospital, Germany), said: "From my perspective as an interventionalist I am happy with these results. They appear to confirm the safety of using prasugrel 5 mg in elderly patients and show there is no need for platelet monitoring even in this high-risk population. For me this is good news."

But Montalescot said he was disappointed that individualization of therapy based on platelet reactivity had failed to improve outcomes. "We know increased platelet reactivity is a risk factor for worse outcomes, but we haven't been able to show a benefit by adjusting this. It is a similar situation to HDL. Maybe platelet reactivity is not a risk factor that can be modified."

In response, Gielen cited the quote: "There is nothing more satisfying that slaying a beautiful hypothesis with the facts."

Further Trials Needed in All-Comer ACS

But coauthor of an accompanying editorial in the Lancet[2], Dr Dirk Sibbing (Ludwig Maximilian University of Munich, Germany), told heartwire from Medscape that he did not believe this was the end of the road for platelet monitoring and that further trials need to be conducted in all-comer ACS patients, not just the elderly, and starting with a higher prasugrel dose.

"The key limitation in ANTARCTIC is the fact that they started with a 5-mg prasugrel dose, and the main adjustment was to a less active antiplatelet strategy of clopidogrel, but prior trials have not shown any difference in clinical outcomes with these two options, " he said.

He added: "For all comers-ACS, if not elderly, the recommended dose, as tested in TRITON-TIMI, is 10-mg prasugrel. This dose has shown superiority for thrombotic risk, but it substantially increased bleeding risk, including fatal bleeds. Potent platelet inhibition is crucial in the acute phase of an ACS but it may not be needed for 12 months post–ACS-PCI. So, we do need larger studies, that start up with a full dose of prasugrel (10 mg) or ticagrelor [Brilinta, AstraZeneca] in ACS patients and deescalate from that." One such trial—TROPICAL-ACS—is now under way and is using platelet-function testing to guide the deescalation.

ANTARCTIC Details

The ANTARCTIC study enrolled 877 patients, aged 75 years or more, who presented with an ACS and underwent coronary stenting. All patients were started on prasugrel (5 mg), with 442 randomized to no adjustment of the medication and 435 to monitoring and treatment adjustment, if needed.

Patients in the monitoring arm received 14 days of the daily 5-mg prasugrel dose and underwent a platelet-function test at day 14 using the VerifyNow assay (Accriva Diagnostics); patients with high on-treatment platelet reactivity (>208 P2Y12 reaction units) or low on-treatment reactivity (>85 P2Y12 reaction units) had their medication adjusted. Patients with platelet reactivity within target levels were continued on prasugrel 5 mg. In patients with high platelet reactivity, the prasugrel dose was increased to 10 mg. In patients with low platelet reactivity, medication was switched to clopidogrel 75 mg. Platelet-function testing was repeated at day 28 for patients who required adjustment after the first testing, with further possible medication adjustment for those outside target values.

After the first platelet-function test, 182 patients (42%) were in the target range of platelet inhibition. When the second test was done, an additional 105 patients had reached the prespecified target.

At the end of the two-step strategy of treatment adjustment, 171 patients (39%) had been switched from prasugrel to clopidogrel for low on-treatment platelet reactivity and treatment was up-adjusted to prasugrel 10 mg in only 16 (4%) patients with high platelet reactivity.

The primary end point of the trial was the composite of cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and further bleeding complication at 1 year.

This end point occurred at a similar rate in both arms of the study: 27.6% in the monitoring group and 27.8% in the conventional group (HR 1.003, 95% CI 0.78–1.29; P=0.98).

There was similarly no significant difference in rates of the main secondary end point (a composite of cardiovascular death, MI, stent thrombosis, or urgent revascularization), which occurred in 9.9% and 9.3%, respectively (HR 1.06, 95% CI, 0.69 to 1.62; P=0.80).

Rates of major bleeding, minor bleeding, or either type of bleed also did not differ between the two groups.

The ANTARCTIC study was funded by Eli Lilly, Daiichi Sankyo, Stentys, Accriva Diagnostics, Medtronic, and Fondation Coeur et Recherche. Montalescot reports grants from ADIR, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celladon, Daiichi Sankyo, Eli Lilly, ICAN, Fédération Française de Cardiologie, Medtronic, MSD, Pfizer, Sanofi, an the Medicines Company and personal fees from Amgen, AstraZeneca, Bayer, Berlin Chimie, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham and Women's Hospital, Cardiovascular Research Foundation, CME Resources, Daiichi Sankyo, Eli Lilly, Europa, Elsevier, Fondazione Anna Maria Sechi per il Cuore, Gilead, Janssen, Lead-Up, Menarini, MSD, Pfizer, Sanofi, the Medicines Company, TIMI Study Group, and WebMD outside the submitted work. Disclosures for the coauthors are listed in the article. Sibbing has received speaker fees and honoraria for consulting from Eli Lilly, Daiichi Sankyo, Bayer Vital, Pfizer, AstraZeneca, and Roche Diagnostics and research grants from Roche Diagnostics. His coeditorialist has no relevant financial relationships.

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