After Gravitas Part 2: Is There a Future for Functional Platelet Testing?
Key Points:
Multiple factors may underlie platelet reactivity levels, including noncompliance
Stent thrombosis may justify functional testing
Reactivity ‘sweet spot’ sought to balance ischemic, bleeding risks
By Kim Dalton
Monday, July 25, 2011
Part 1 addressed possible explanations for the negative findings of the GRAVITAS trial and the implications for current clinical practice. In Part 2, the story continues with a discussion of the limitations of functional platelet testing and the potential risk of using it to guide therapy as well as some arguments in favor of current testing and hints of a wider future role.
The failure of the GRAVITAS trial to support a strategy of intensified clopidogrel therapy to overcome high residual platelet reactivity following PCI prompted many experts to conclude that, for the time being, there is no justification for routine testing.
A key reason is that a host of factors may be contributing to a patient’s baseline platelet reactivity and response to antiplatelet therapy, including:
Comorbid conditions like diabetes
Age
Body weight
Smoking status
Compliance with the prescribed antiplatelet regimen
Concomitant medications such as proton pump inhibitors
Genotype (including complicated interactions between variant alleles and heterozygosity vs. homozygosity)
An underlying question, raised by Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), among others, is if ischemic events can occur even in patients with low platelet reactivity, is the latter truly a modifiable risk factor or is it more in the nature of a risk marker?
Numerous studies have shown that high on-treatment platelet reactivity as measured by functional testing correlates with increased thrombotic risk. But in the POPULAR trial (Breet NJ, et al. JAMA. 2010;303:754-762), a head-to-head comparison of 6 major assays, the predictive value of the 3 tests with validated cutpoints was relatively modest.
Exceptions to the ‘No Test’ Rule
Nonetheless, a recent white paper (Bonello L, et al. J Am Coll Cardiol. 2010;56:919-933) outlined certain situations in which it is appropriate to “consider” platelet function testing to help determine antiplatelet therapy: in patients with a history of stent thrombosis and prior to high-risk PCI.
The bottom line is that, for the most part, therapy should be guided by a patient’s presentation, not testing, Dr. Bhatt said, and he offered 2 scenarios from opposite ends of the risk spectrum to illustrate the point.
A Test-Guided Algorithm
At UCSD Medical Center (San Diego, CA), however, testing has been given a more liberal role. Several years ago, Ehtisham Mahmud, MD, and colleagues developed an algorithm to help make decisions about the best antiplatelet therapy for different patients. The algorithm is intended as a rough guide and has evolved as more trial data have become available, Dr. Mahmud said.
After PCI, all patients’ platelet reactivity is tested with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), he reported. If they are not already on a thienopyridine, patients with ACS and diabetics go straight to prasugrel, unless they have clinical characteristics that put them at increased bleeding risk (primarily age > 75, low BMI, a history of TIA or stroke).
Nondiabetic elective patients are given clopidogrel (600 mg loading dose, 75 mg daily). Among those who are clearly compliant with therapy yet do not respond (ie, show less than 30% platelet inhibition), a key factor in deciding whether or not to switch them to prasugrel is their angiographic characteristics, said Dr. Mahmud. “In patients with a straightforward focal lesion, and inhibition of 15% or 20%, in the past we would have switched them to prasugrel,” he observed. “Since GRAVITAS, I would probably keep them on clopidogrel. But if I don’t see any meaningful inhibition based on VerifNow measurement, I will switch these patients to prasugrel.”
On the other hand, compliant clopidogrel nonresponders who are undergoing high-risk PCI, such as for left main stenosis or multivessel disease, are candidates for prasugrel, Dr. Mahmud said. The same applies to patients who present with an event on clopidogrel or have had stent thrombosis, he added.
Another testing outpost is nearby Scripps Clinic in La Jolla, CA. There, Paul S. Teirstein, MD, says that even in the wake of GRAVITAS, he still tests nearly every PCI patient on standard-dose clopidogrel. “I might even start testing my prasugrel patients considering the new data that have come out,” he added in a telephone interview with TCTMD, alluding to the recent study showing that about one-quarter of ACS patients respond inadequately to prasugrel (Bonnello L, et al. J Am Coll Cardiol. 2011;58:467-473).
Limitations of Functional Testing
Beyond the issue of clinical validation, functional testing itself is far from straightforward. According to Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), to be useful in routine practice, a point-of-care test must:
Be simple to use
Provide quick results
Be easy to interpret
Be relatively inexpensive
Searching for a ‘Sweet Spot’
For most researchers, the holy grail of antiplatelet testing is identifying a therapeutic window—a range of platelet reactivity that will safeguard a patient between thrombotic risk on the high end of reactivity and bleeding risk on the low end.
Even more encouraging, a kind of therapeutic window of reactivity emerged from the study by Campo et al. Analysis showed that both ischemic and bleeding events were minimized when PRU values fell between 86 and 238.
However, a reactivity ‘sweet spot’ will likely vary not only with the specific functional test used but also with patients’ clinical presentation and the time from PCI, Dr. Angiolillo noted. For example, the low platelet reactivity required to prevent thrombotic events during the periprocedural period may be a liability 6 months later. And the optimal levels are likely to differ for elective and emergent PCI.
Nonetheless, if reliable therapeutic windows can be established, “the role of functional testing will be huge,” Dr. Mahmud commented. Furthermore, when in the near future clopidogrel becomes generic, platelet testing is likely to be used to show when a high-risk patient is responding to the drug and therefore does not need to be switched to a more potent—and more expensive—agent, he observed.
The Clinician’s Dilemma
Despite the setback of GRAVITAS—and the controversy surrounding the clinical relevance of genotyping—physicians understandably remain eager to find ways to minimize individual patients’ post-PCI risk.
Although GRAVITAS is important, “no one study in isolation answers every question. We’ll need a lot more and hopefully larger studies to really nail down these issues,” he concluded.
One area that Dr. Mahmud believes deserves particular attention is the influence of angiographic complexity on antiplatelet response. “Because we’re treating more and more complex lesions, it will be interesting to see how the degree of platelet inhibition [is affected by different levels of complexity] and how that [impacts] outcomes,” he said. “Arguably, if a patient has a simple focal lesion, even if he presents with ACS, you may not need very high inhibition of reactivity. And vice versa, you could have an elective patient with a very complicated lesion where you would need high platelet inhibition.”
Dr. Kleiman called for similar research. “I would like to see high reactivity defined for patients in the highest stratum of risk—those with multiple long stents, ACS, or acute MI,” he said. “Those are the folks about whom we have the most questions.”
Meanwhile, Dr. Angiolillo stressed that practitioners should continue to be guided by consensus statements, the therapeutic indications that have been validated in large clinical trials, and above all by good clinical judgment.
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, Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.