After GRAVITAS: Is There a Future for Functional Platelet Testing?
Negative findings evoked multiple possible explanations
Much research needed before test-guided antiplatelet therapy enters the clinic
By Kim Dalton
Monday, July 18, 2011
In a 2-part series, TCTMD will explore how the GRAVITAS trial is influencing the field of functional platelet testing. Part 1 summarizes the trial and its aftermath, including explanations for the results and remaining issues. Next up, part 2 will address the risks of using platelet function tests to guide therapy in lieu of randomized trial data and discuss their future in clinical practice.
At the American Heart Association Scientific Sessions 2010 this past November in Chicago, one of the most keenly awaited late-breaking trials delivered a blow to the attractive concept of adjusting antiplatelet therapy following percutaneous coronary intervention (PCI) based on functional measurement of platelet reactivity.
GRAVITAS (Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety) promised to answer the question of whether a relatively straightforward strategy for managing the almost one-third of patients who have high platelet reactivity despite receiving standard dual therapy after PCI—and thus are at substantially increased risk of thrombotic events—was in fact effective.
The trial had the potential to change practice. After mixed signals from several small observational studies, here were data from the first large randomized trial to close the circle between pharmacodynamic and clinical data by rigorously testing whether adjusting clopidogrel dose based on results of a point-of-care functional test would improve patient outcomes.
The answer, reported by lead investigator Matthew J. Price, MD, of Scripps Clinic (La Jolla, CA), was no, bringing with it larger implications for the future of this nascent field.
Disappointing Results—and Plenty of Explanations
In the targeted cohort with high on-treatment reactivity, at 6 months rates of the primary endpoint, a composite of cardiovascular death, MI, or stent thrombosis, were identical for the high- and standard-dose clopidogrel groups: 2.3%.
For the trial, almost 5,500 patients with stable or unstable CAD underwent DES implantation and received a 600-mg loading dose of clopidogrel (if they were drug naïve). Testing 12 to 24 hours later using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) identified 2,214 patients (41%) with high residual reactivity, defined as a P2Y12 reaction unit (PRU) value equal to or above 230. That cohort was then randomized to continue on the standard 75-mg maintenance dose or receive another 600-mg loading dose and then 150 mg daily, both for 6 months.
While GRAVITAS is clearly not the final word on the use of functional testing to guide therapy, several commentators noted, at the least it invalidated the particular strategy tested and put routine point-of-care platelet testing on hold. Meanwhile, they said, it is important to try to understand why the trial was negative in order to move forward. And there has been no shortage of proposed explanations, with attention directed at nearly every aspect of the trial design, from the patients studied to the antiplatelet regimen used and the reactivity cutpoint chosen.
Analysis confirmed that the more aggressive antiplatelet regimen did in fact have a pharmacodynamic impact. At 30 days after PCI, platelet reactivity had decreased in both arms, but the decline was steeper in those who received the double clopidogrel dose, and the difference remained largely unchanged at 6 months. At 1 month, high residual reactivity persisted in only 40% of the high-dose group compared with 62% of the standard-dose group (P < 0.001), for an absolute reduction of 22%.
Significantly, however, even in the high-dose arm, the absolute reduction in PRU was modest, declining from a median of about 280 at baseline to about 200, Dr. Price reported. Moreover, the relatively small absolute difference in median platelet reactivity between the 2 arms—about 40 PRU—was reflected in the fact that rates of GUSTO severe and moderate bleeding were similar (1.4% in the high-dose arm vs. 2.3% in the standard-dose arm; P = 0.10).
The investigators’ power assumptions—a 5% event rate in patients on standard clopidogrel and a 50% risk reduction with high-dose drug—also came under fire as being overly optimistic. The low event rate observed in the standard-dose arm of only 2.3% set a near-impossible bar for double-dose patients to surpass, several commentators suggested. They added that increasing the sample size and/or lengthening follow-up might boost the event rate, improving the odds of seeing a difference between the treatment groups, but it would also expose even more patients to the possibility of bleeding when there was no hint of ischemic benefit.
In fact, after GRAVITAS, many experts were pinning their hopes on the more aggressive strategy of the TRIGGER-PCI trial. It not only set a PRU threshold of 208 but was testing the more potent antiplatelet agent prasugrel in elective PCI patients with high platelet reactivity on clopidogrel.
Nonetheless, other, ongoing randomized trials are exploring different approaches to test-guided therapy and may provide insights into the question of whether functional testing holds any future role. These include:
ARCTIC, in which clopidogrel dosage will be adjusted for elective patients with a suboptimal response to initial therapy based on a VerifyNow cutpoint of 235 PRU
DANTE, in which ACS patients will be randomized to a standard or double maintenance dose of clopidogrel based on VerifyNow-measured residual reactivity
TARGET PCI, in which PCI patients determined by genotyping or serial functional testing (230 PRU cutpoint) to have high residual platelet reactivity will be switched to prasugrel
Unresolved Issues
Supporting that view are results of a recent Italian trial (Campo G, et al. J Am Coll Cardiol. 2011;57:2474-2483) in which high on-clopidogrel platelet reactivity (defined as a PRU of ≥ 235) at baseline frequently fell below that threshold by 1 month. Moreover, 1-month reactivity levels were found to be stronger predictors of long-term outcomes.
Given this temporal variability, a proposed way to rescue a test-guided antiplatelet strategy is to treat patients to a target level of reactivity, adjusting therapy based on the results of serial testing. A hint that such an approach might work comes from a small, nonrandomized study of ACS patients undergoing PCI (Bonello L, et al. J Am Coll Cardiol. 2010;56:1630-1636). Among poor responders to a 600-mg loading dose (about one-third of whom carried at least 1 loss-of-function CYP2C19 allele), the loading dose was repeated up to 4 times—guided by reactivity monitoring—until 88% of them reached ‘adequate’ platelet inhibition (defined as a VASP [vasodilator stimulated phosphoprotein] index < 50%).
The larger hope of using testing to guide therapy, however, faces many hurdles. “I’ve always felt there will ultimately be some role for testing, but we need to wait for the evidence rather than just act on gut feelings,” Dr. Bhatt stressed, offering as a cautionary example the discredited therapy for premature ventricular contractions (PVCs). Suppressing these dangerous arrhythmias seemed to make sense, he explained. The only problem was that the drug used for that purpose ended up causing even worse arrhythmias.
Similarly, “it’s logical to think that responding to [inadequate] antiplatelet inhibition on a point-of-care assay [with higher antiplatelet doses or a more potent drug] should improve patient outcomes,” Dr. Bhatt said. “But it’s tricky, because more isn’t always better. There may also be more bleeding.” Furthermore, the risk-benefit ratio could vary widely based on patient presentation—for example, elective vs. urgent PCI with a DES, he added.
The second half of this feature, which will appear Monday, July 25, will discuss how these debates play out in clinical practice.
Sources:
1. Price MJ. Standard versus high-dose clopidogrel according to platelet function testing after PCI: Results of the GRAVITAS trial. Presented at: American Heart Association Scientific Sessions; November 16, 2010; Chicago, IL.
2. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA. 2011;11:1097-1105.
3. Gurbel PA and Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.