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.

In fact, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD in a telephone interview, “I don’t think [the choice of antiplatelet strategy] will ever boil down to something as simple as a test spitting out a result and that dictating our actions.”

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.

“It’s simply not the case that results from a platelet assay trump all the other factors that go into risk assessment,” Dr. Bhatt stressed. “A test could potentially be complementary to conventional risk stratification, and it might be of some clinical utility. But unless you can change therapy and improve outcomes based on [the test], it’s not very useful.”

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.

“If someone has had multiple stent thromboses, you don’t have the luxury of waiting for evidence from a randomized clinical trial, so I likely would test,” Dr. Bhatt admitted.

“Even so, I wouldn’t consider the test in isolation,” he added. “And before doubling the clopidogrel dose or switching to prasugrel, I would make sure the patient was really taking their medicine.” If a patient was skipping doses, thereby skewing reactivity readings, intensifying antiplatelet therapy might wind up inducing a bad bleed, Dr. Bhatt observed. And even nuisance bleeding could lead to discontinuation of therapy, with potentially fatal consequences.

Neal S. Kleiman, MD, of the Methodist DeBakey Heart and Vascular Center (Houston, TX),  agreed that stent thrombosis is an instance in which testing might come into play. But, in a telephone interview with TCTMD, he advised against testing until the patient has “cooled down.” And even then, he said, “if you have someone with what you thought were well-placed stents and you tested their platelets and found they were responsive to whatever regimen you were using, would you believe [the results]? Or would you think, ‘I’m just going to go ahead and put them on 10 mg prasugrel so we don’t have to do this again’? Dr. Kleiman likened testing for platelet reactivity in this situation to testing cholesterol levels in someone who has had an MI. “The odds are overwhelming that you’re going to put them on a statin, so why bother?” he said.

“I might worry a bit about bleeding risk,” he admitted, “but if somebody has had stent thrombosis, then the balance has already shifted toward [the need to prevent further] thrombosis.”

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.

“For example, with an 80-year-old who undergoes elective stenting for atypical angina and is doing well clinically, I wouldn’t measure platelet reactivity [and even less] intensify antiplatelet therapy based on the result,” Dr. Bhatt said. “On the other hand, for somebody who comes [into the hospital] with a huge thrombus burden, an LAD infarct, and an akinetic anterior wall, if he is at low bleeding risk, he probably should have intensified antiplatelet therapy. But I wouldn’t need a point-of-care test to tell me that.

“It’s premature to personalize therapy based on anything other than phenotype—that is, clinical characteristics such as age, renal function, diabetic status, bleeding risk, that sort of thing,” he concluded.

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).

Dr. Teirstein tests patients with VerifyNow before discharge and, if they are poor responders, switches them to a double dose of clopidogrel or to prasugrel if they qualify for the more potent thienopyridine. Then in 30 days, he brings them back to check their response to the new regimen.

“The GRAVITAS strategy clearly didn’t work,” he acknowledged, “but if we can achieve adequate platelet inhibition, patients do better. I am more comfortable when their PRU value is less than 200.

“Reactivity testing seems like a very simple, low-cost way of gaining some more information about your patient, so why not?” he continued. “I understand that it’s not justified by a randomized trial, but a lot of things we do don’t have randomized data to support them. We do the best we can with the data we have. And the data we have right now teaches us that patients do better if their PRU is low.

“I’ve never bought the argument that we’re going to harm some patients by checking their PRU and trying to respond to it,” he commented. “Talk about lack of evidence—there’s no evidence for that.” If a patient is a candidate for [prasugrel], then the bleeding risk should be acceptable, he observed.

Dr. Teirstein says he likes to ask those who oppose testing, “Suppose I had just put a stent in your LAD and your PRU value was 300, would you want me to try to get it down? If they’re honest, after a little stumbling, they usually say, ‘Well, maybe.’”

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

But functional testing faces a more fundamental limitation, he told TCTMD in a telephone interview, because platelets can be activated by several different pathways, and none of the current tests accounts for all of them. “For example, when we measure P2Y12, that’s just one pathway,” he said, “so even if a patient has an optimally inhibited P2Y12 signaling pathway, that doesn’t mean he is not at risk of a recurrent ischemic event because other pathways may be upregulated.”

In the same vein, Dr. Bhatt decried the common failure of testing advocates to appreciate the complexity of assessing in vivo platelet reactivity. “For example, there is a whole coagulation cascade that we can’t ignore, and multiple interrelated pathways,” he said. “And then you have to incorporate [the effects of] flow [in the vessels]. A single test just doesn’t capture all of that.”

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.

Although some consensus exists regarding cutpoints for ischemic risk—at least for selected assays (eg, Bonello L, et al. J Am Coll Cardiol. 2010;56:919-933)—few studies have attempted to establish cutpoints for bleeding risk. Yet the need to define such thresholds is becoming more urgent as potent new antiplatelet agents such as prasugrel and potentially ticagrelor come online, Dr. Angiolillo said. And in fact some data on this equally risky side of the reactivity coin have begun to emerge.

For example, in a recent study of PCI patients pretreated with 600 mg clopidogrel, ‘enhanced’ drug response, as assessed by the Multiplate analyzer (Verum Diagnostica, Munich, Germany), was linked to increased TIMI major bleeding (Sibbing D, et al. J Thromb Haemost. 2010;8:250-256). Analysis suggested an optimal cutpoint to predict bleeding risk of 188 aggregation units (AU) per minute. Moreover, in the ARYMYDA-BLEEDS trial (Patti G, et al. Am J Cardiol. 2011;Epub ahead of print), point-of-care testing before PCI identified patients at increased risk of major bleeding and entry-site complications. The optimal cutpoint was calculated to be ≤ 189 PRU by VerifyNow testing. And in the ongoing ARCTIC trial, in 1 arm clopidogrel dosing is being adjusted up or down based on platelet reactivity monitored by the VerifyNow assay.

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.

“There is great allure and great promise to personalized medicine, and I hope it does pan out in some form,” Dr. Bhatt said. “But whenever there are contradictory data and experts giving contradictory interpretations, it’s tough for clinicians to know what to do. My bottom-line message is: For the time being, it is premature to test patients routinely.”

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.

 

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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.

 

 

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• GRAVITAS: ‘Personalized’ Clopidogrel Dosing Yields No Benefits in PCI Patients
• High-Dose Maintenance Clopidogrel Lowers Platelet Reactivity, Other Risk Factors
• Dose Escalation Overcomes Poor Clopidogrel Response in Most Patients