ARCTIC: Bedside Platelet Monitoring Fails to Help DES Patients

LOS ANGELES, CA—In another setback for the clinical utility of platelet-function monitoring, a large, randomized trial has failed to show any improvement in outcomes using the testing strategy to guide treatment in patients receiving drug-eluting stents (DES). The results, presented November 4, 2012, at the American Heart Association Scientific Sessions, were published simultaneously online in the New England Journal of Medicine.

For the ARCTIC trial, researchers led by Gilles Montalescot, MD, PhD, of the Institute de Cardiologie Hôpital Pitié-Salpêtrière (Paris, France), randomized 2,440 patients scheduled for coronary stenting at 38 centers in France to 1 of 2 strategies:

• Bedside platelet function monitoring (VerifyNow, Accumetrics, San Diego, CA) with drug adjustment in poor antiplatelet therapy responders (n = 1,213)
• No monitoring/drug adjustment (n = 1,227)

P2Y12 monitoring was performed in the cath lab prior to stent implantation and 2 to 4 weeks later. Baseline characteristics were similar for the 2 groups, with 27.0% of patients presenting with ACS but no ST-segment elevation.

Platelet Reactivity Halved

In the monitoring group, high platelet reactivity was present in about one-third (34.5%) of those taking clopidogrel, and in 7.6% of those taking aspirin. In these patients, high platelet reactivity led to an additional bolus of clopidogrel (80.2%), prasugrel (3.3%), or aspirin in addition to GP IIb/IIIa inhibitors during the procedure. When measurements of platelet reactivity were repeated 2 to 4 weeks later, the percentage of patients with poor response to P2Y12 inhibitors was cut roughly in half (15.6% vs. 34.5% at the time of the procedure; P < 0.001). At this visit, further adjustment of antiplatelet therapy was performed for those in the monitoring group who showed inadequate platelet inhibition.

Despite reducing platelet reactivity, the strategy of therapy adjustment based on platelet function monitoring did not lead to any improvement in the primary composite endpoint of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year, or the secondary composite of stent thrombosis or urgent revascularization compared with patients who received no monitoring. The same was true for the individual component endpoints (table 1).

Table 1. Primary and Secondary Outcomes at 1 Year

Major bleeding (2.3% with monitoring vs. 3.3% without monitoring; P = 0.15) and minor bleeding (1.0% vs. 1.7%; P = 0.12) were also similar between groups.

“This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring,” Dr. Montalescot concluded.

Shades of GRAVITAS?

The first major, randomized trial to test the utility of platelet function monitoring in guiding therapy was GRAVITAS. That trial, led by Matthew J. Price, MD, of the Scripps Translational Research Institute (La Jolla, CA), looked at platelet reactivity using the VerifyNow P2Y12 assay in 5,429 stable or unstable CAD patients who had received DES.

Among them, 2,214 subjects were found to have high platelet reactivity between 12 and 24 hours after DES implantation. This group was randomized to either high-dose (n = 1,109; 600-mg initial dose and 150 mg daily thereafter) or standard-dose (n = 1,105; no additional loading dose and 75-mg daily thereafter) clopidogrel.

At 6 months, the rate of the primary endpoint (composite of death from cardiovascular causes, nonfatal MI, or stent thrombosis) and its individual components were similar in high-dose and standard-dose patients (2.3% in both arms; P = 0.97).

Dr. Montalescot cited several reasons why the ARCTIC trial may have failed to prove the efficacy of platelet function monitoring in guiding treatment in DES patients. First of all, the patient population was fairly high risk, with a higher mortality at 1 year than usually observed in elective stenting patients. Secondly, the proportion of poor responders to clopidogrel in ARCTIC was similar to that observed in GRAVITAS, but a different cut-off may have been more discriminating. Third, there was not one single strategy for dose adjustment in ARCTIC, but several, ie, dose or therapeutic agent could be changed. And lastly, high platelet reactivity may be a poor surrogate for guiding therapeutic decisions.

In fact, future trials may prove the efficacy of platelet function monitoring in different populations than the one in the current study. But in the meantime, “our results do not support the routine use of platelet function monitoring in patients undergoing stenting,” Dr. Montalescot said.

For Research Purposes Only

Commenting on the trial, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), agreed, noting that several trials in addition to ARCTIC and GRAVITAS, including TRIGGER PCI, ADEPT DES, and PRECLOSE 2 ACS, have shown no benefit from antiplatelet dose adjustment based on platelet function monitoring in PCI patients. The only exception to this was the recent MADONNA trial.

“At the population level, it has been consistently demonstrated that clopidogrel hyporesponsiveness predicts ischemic risk, but that optimization of platelet function testing results by adjusting therapy has not been associated with better clinical outcome,” Dr. Bates said. “At the patient level, platelet function testing is not sensitive or specific enough to guide tailored antiplatelet therapy.

“I will conclude as others before me have that platelet reactivity at this point appears to be a risk marker,” Dr. Bates continued, “very useful for research studies, but it does not appear to be a modifiable risk factor that will impact the decision whether or not to adjust therapy.”

Study Details

High platelet reactivity on thienopyridine therapy was defined as ≥ 235 PRU, ≤ 15% inhibition compared with baseline, or both. If high platelet reactivity during treatment with clopidogrel was identified, the protocol called for administration of GP IIb/IIIa inhibitors and an additional loading dose of clopidogrel (≥ 600 mg) or a loading dose of prasugrel (60 mg) before the procedure, followed by 150-mg clopidogrel or 10-mg prasugrel maintenance. At 14 to 30 days after stent implantation, patients with high platelet reactivity during treatment with clopidogrel were switched to prasugrel 10 mg or given a 75-mg increase in the maintenance dose of clopidogrel.

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Source:
Collet J-P, Cuisset T, Rangé G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;Epub ahead of print.

 

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• Some Clopidogrel Poor Responders Helped by Higher Dosing