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Despite prasugrel’s greater potency and faster action compared with the older antiplatelet agent clopidogrel, platelet reactivity testing after a loading dose of the newer third-generation thienopyridine shows suboptimal inhibition in about 1 in 4 patients with acute coronary syndromes (ACS) following percutaneous coronary intervention (PCI). Furthermore, high on-treatment platelet reactivity leads to more thrombotic events at 30 days, according to a prospective multicenter study published in the July 26, 2011, issue of the Journal of the American College of Cardiology.

Laurent Bonello, MD, of Hôpital Universitaire Nord (Marseille, France), and colleagues enrolled 301 patients who underwent successful PCI for ACS (42.5% STEMI) and received prasugrel as antiplatelet therapy (60-mg loading dose and 10 mg daily for 1 year). Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) assay on blood drawn between 6 and 12 hours after drug loading.

High on-treatment platelet reactivity was defined as a VASP index of at least 50%. In the overall cohort, the mean VASP index was 34.3 ± 23.1%, but there was wide variability among individuals (1% - 82.8%). Although the majority of patients showed adequate inhibition, 25.2% were found to have high residual reactivity. On the other hand, about one-third had very low VASP values (< 20%).

High Reactivity Means More Thrombotic Events

At 30-day follow-up, more patients with high on-treatment reactivity met the primary composite endpoint (cardiovascular death, nonfatal MI, or Academic Research Consortium-defined stent thrombosis) than did good responders. In addition, 3 poor responders experienced nonfatal definite stent thrombosis. Although 4 good responders had TIMI bleeding events (2 major requiring transfusion and 2 minor) compared with only 1 minor bleed in patients with high reactivity, the difference was not significant (table 1).

Table 1. One-Month Outcomes by Platelet Reactivity Level

VASP levels were higher in patients experiencing recurrent thrombotic events compared with those free of events at 1 month (64.4 ± 14.4% vs. 33.4 ± 22.7%; P = 0.001). In univariate analysis, the only factors significantly associated with thrombotic events were the VASP index (P = 0.001) and hypercholesterolemia (P = 0.032). No difference was seen in VASP index between patients with or without TIMI non-CABG-related bleeding (30 ± 17.8% vs. 34.3 ± 23.1%; P = 0.70).

Similarly, Kaplan-Meier analysis showed that patients with high on-treatment reactivity had worse 1-month outcomes than good responders (9.2% vs. 0.4%; log-rank P < 0.001). However, no difference emerged in TIMI bleeding between patients above or below the reactivity cutpoint of 50% (P = 1.00). Demographic, clinical, and angiographic factors were similar between the 2 groups, except for relatively fewer men in the high on-treatment reactivity group (81.6% vs. 92% in the good responders; P = 0.007).

The optimal cutoff value of the VASP index was determined to be 53.5%, yielding a positive predictive value of 10.4% and a negative predictive value of 99.6%.

Low Reactivity a Lingering Concern

The authors point out that although a sizable number of patients had very low platelet reactivity after prasugrel loading, no relationship emerged between reactivity level and bleeding risk. Nonetheless, they caution, previous studies involving clopidogrel have found an association between excessive inhibition and bleeding complications. “These findings suggest that there may [be] a therapeutic window of [thienopyridines] to reach to prevent thrombotic events and not increase the bleeding risk,” the investigators write.

Dr. Bonello and colleagues suggest that, based on the current findings, “prasugrel therapy may require [platelet reactivity] monitoring to enable optimal [platelet reactivity] inhibition to be achieved, which may lead to improved outcomes in all patients.”

In a telephone interview, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD that he was not surprised that one-quarter of prasugrel-treated patients showed high platelet reactivity. But many physicians may be, he said, since until now most attention in regard to poor response has focused on clopidogrel.

High Reactivity: It’s Not Just the Drug

Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), similarly observed in an e-mail communication with TCTMD that even with prasugrel, it increasingly seems that high on-treatment platelet reactivity “is an important variable to measure patient response to drug [therapy].”

“Unfortunately,” he added, “[reactivity] thresholds may vary by test, and the result is influenced by clinical syndrome, patient factors, and time of measurement, not just the antiplatelet drug.”

Dr. Bates also said he wished the researchers had continued platelet reactivity measurements for 4 days, as they did in an their study on repeat clopidogrel loading doses (Bonello L, et al. J Am Coll Cardiol. 2008;51:1404-1411). Such a protocol could have helped determine “whether there was earlier suppression [of reactivity] in low responders than there was with clopidogrel,” he noted.

Dr. Bhatt agreed that clinical setting plays a key role in platelet reactivity. He pointed out that, with the exception of genetic polymorphisms (which affect the bioavailability of clopidogrel but not prasugrel), all the factors that contribute to variability in platelet response to clopidogrel likely also apply to response to prasugrel—just to a lesser degree.

Moreover, Dr. Bhatt noted, “[y]ou would think that if someone had high on-treatment platelet reactivity, their risk of bleeding should be lower and risk of ischemic events should be higher. And vice versa. But that has not been consistently seen in studies. In fact, if anything, it seems like patients who bleed have a higher rate of ischemic events.

“It’s a very complex issue and shows we don’t really understand what predisposes patients to bleeding or ischemic events as precisely as we’d like to,” he commented.

Practicing in a ‘Gray Zone’

Dr. Bhatt said it is difficult to know whether the reactivity testing results are clinically important.

“As with clopidogrel studies, high on-treatment reactivity is associated with a high rate of ischemic events, so it’s certainly a marker of future risk. If your platelets are more reactive than other patients’, you are worse off regardless of whether you’re on clopidogrel or prasugrel,” he said. “But is it really the drug that’s at fault or the patient’s ‘angry platelets?’ I think what we’re identifying here is primarily high-risk patients.”

According to Dr. Bhatt, the key clinical question remains unanswered: Is there a way to alter therapy based on knowledge of platelet reactivity that improves patient outcomes? “To date, no one has shown that satisfactorily, and if anything, the negative findings of GRAVITAS would argue against it,” he noted.

“The study is something researchers can build on and leaves the door open for more potent periprocedural inhibition of platelet reactivity,” Dr. Bhatt acknowledged. But until a positive randomized study is reported, “we’re left in a kind of gray zone where we have provocative data [but no clear clinical strategy]. My fear is that some physicians might overinterpret this study and if a test shows high on-treatment reactivity double the prasugrel dose, for example. Not only might that not be helpful, it might be harmful. Especially when we’re talking about more potent agents, we have to be really cautious about the bleeding risk of an untested strategy.”

Study Details

The great majority of the study patients were men (88.7%), with a mean age of 58.1 years. Almost one-quarter (23.3%) had diabetes.

DES or BMS were used according to French Society of Cardiology guidelines. Functional testing was performed using Platelet VASP kits (Diagnostica Stago, Asnières, France).

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