Platelet Function Testing: Time to Get Personal
While clopidogrel is a successful antiplatelet drug for PCI patients, its ineffectiveness in certain patient subsets has recently been documented, spurring an FDA boxed warning. Testing patients’ platelet responsiveness or their genotype has shown success, but which tests are most effective and efficacious? Further compounding these cath lab choices, newer antiplatelet agents loom as potential game changers.

Why personalize treatment?

About 30 percent of PCI patients don’t respond to standard clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) loading and maintenance doses. Research also suggests that at least 20 to 30 percent of PCI patients have high platelet reactivity, cites Paul Gurbel, MD, director of cardiovascular research at the Sinai Center for Thrombosis Research in Baltimore (J Am Coll Cardiol 2010;56:919-933). Laurent Bonello, MD, from the cardiology department at Hôpital Universitaire Nord in Marseille, France, postulates that even more than one-third of PCI patients have a CYP2C19*2 loss-of-function allele, based on platelet reactivity testing. “This is not an insignificant number of patients,” Bonello says.

Due to the lack of consensus and guideline-recommended therapy, researchers are scrambling to better understand and treat this vulnerable patient subset. These patients may require a personalized approach. “Rather than change therapy for the entire population and increase the risk of bleeding, we can select the particular patient subset at greatest ischemic risk for high-dose therapy or stronger P2Y12 inhibitions to provide the greatest net clinical benefit,” says GRAVITAS Principal Investigator Matthew J. Price, MD, director of the cardiac cath lab at Scripps Clinic in San Diego.

While GRAVITAS is testing the efficacy of a standardized increase in clopidogrel maintenance dose in patients with high platelet reactivity, others advocate dose titration. “The data suggest that the ‘one-size-fits-all’ approach to administering clopidogrel is not appropriate. Therefore, tailored therapy is necessary to avoid thrombotic or bleeding events,” says Bonello.

Meanwhile, some discrepancy exists about whether the FDA boxed warning was premature or perpetuated confusion about testing. For clopidogrel to be effective, enzymes in the liver (particularly CYP2C19) must metabolize the drug to its active form. Patients who are poor clopidogrel metabolizers do not effectively convert Plavix to its active form, the FDA writes. In these patients, clopidogrel has less effect on platelets and, therefore, less ability to prevent heart attack, stroke and cardiovascular death.

“The FDA’s position is reasonable in that clopidogrel’s effect is mediated by an active metabolite, and poor metabolizers have significantly less active metabolite generation than extensive metabolizers, resulting in the inability of the drug to achieve its intended effect,” Price says. He adds that the FDA warning is “merely informational” and does not mandate genotyping, and did not even mention phenotyping, or platelet testing.  

Yet, questions remain about whether this warning has affected real-life clinical practice. “Clinicians haven’t responded to the boxed warning because they do not routinely genotype PCI patients,” Gurbel says. “Also, the FDA dropped the ball by not mentioning platelet function testing. Numerous studies demonstrate the importance of measuring platelet reactivity to gauge post-PCI risk.”

The warning also has been criticized for addressing only patients with two loss-of-function alleles, and providing no information for heterozygotes.

Price suggests that while the boxed warning “may not have changed many people’s practices, it has increased awareness of the variability of platelet responsiveness to clopidogrel.”

Phenotyping vs. genotyping

To inform this burgeoning field, more data are needed to better determine the benefits of testing patients’ responsiveness to clopidogrel either through genetic testing or platelet reactivity testing. Price notes that there is “general confusion” about the two types of tests, and they are “not interchangeable.”

However, there may be a “complementary role for genotyping and phenotyping,” Gurbel says, “but without concrete data, cath lab decisions can’t be based only on supposition. Hopefully, forthcoming trials will answer some of these questions.”

TARGET-PCI, an ongoing, prospective study led by Gurbel, will use the VerifyNow P2Y12 platelet test (Accumetrics), but the researchers also will genotype patients (Verigene, Nanosphere) who are clopidogrel naïve to determine therapy. Instead of using high-maintenance-dose clopidogrel, as used in GRAVITAS, TARGET-PCI will administer prasugrel (Effient, Eli Lilly/Daiichi Sankyo) for carriers of the *2 allele.

“One advantage of genetic testing over phenotyping is that the test can be administered before antiplatelet therapy has begun,” notes Guillaume Paré, MD, director of the genetic and molecular epidemiology lab at McMaster University in Hamilton, Ontario.

In TARGET-PCI, if patients present already on clopidogrel, researchers will phenotype them using VerifyNow, with the cutoff value of 240 P2Y12 reaction units (PRU). If patients have platelet reactivity above the cutoff value, they will be placed on prasugrel. If not, they will receive a standard dose of clopidogrel. The guided arm of TARGET-PCI  will receive either a genotype or a phenotype test to determine initial antiplatelet therapy, and the unguided arm will receive standard therapy. The results are expected to be available by late 2012.

Until there are more “solid data” comparing genetic with platelet function testing, Paré sees the tests as a matter of preference and to be used in a “complementary” manner, if at all.

Yet, in the short term, it appears as if platelet reactivity testing is gaining popularity among clinicians. “Whereas neither genotyping nor platelet function tests alone adequately describe the global risk profile of an individual patient treated with clopidogrel, point-of-care platelet function testing to identify high-risk patients combined with CYP2C19 genetic testing may be more effective in identifying high-risk individuals for alternative antiplatelet therapies,” according to a consensus white paper, of which Bonello was the lead author. “Ultimately, prospective randomized clinical trials will be needed to test specific personalized antiplatelet algorithms to provide the evidence base necessary for widespread adoption into clinical practice” (J Am Coll Cardiol 2010;56:919-933).

Phenotyping for now

In lieu of definitive data, various studies have spoken to the benefits of platelet reactivity testing, with GRAVITAS poised as a game changer.

In a recent study, Bonello et al sought to address the question of whether patients who were carrying a loss-of-function allele could reach optimal platelet inhibition using dose adjustment with platelet reactivity monitoring (J Am Coll Cardiol 2010.07.004). Using the vasodilator-stimulated phosphoprotein (VASP) index, researchers defined a good response to clopidogrel below 50 percent, which was the cutoff value. Below 50 percent, the patient was deemed to have acceptable platelet inhibition and PCI was performed. In patients carrying CYP2C19*2 and exhibiting high platelet reactivity after a first 600 mg loading dose of clopidogrel, dose adjustment was performed by using up to three additional 600 mg loading doses to obtain a VASP index below 50 percent.

“We found that regardless of the genotype, a dose-adjustment strategy is effective in 88 percent of patients,” Bonello says. “If it’s regardless of genotype, it probably means that platelet reactivity can be used alone without genotyping to tailor therapy and improve outcomes.”

However, many are awaiting the results of GRAVITAS to assess the importance of platelet reactivity testing. GRAVITAS, which will be presented this month at the AHA.10 scientific sessions, enrolled approximately 2,800 patients, whose platelet function was assessed 12 to 24 hours after PCI using the VerifyNow P2Y12 test. The patients were assigned to one of three arms, according to platelet function. If the patients PRU was higher than 230, they were classified as high platelet reactivity and randomized to one of two arms: high-dose Plavix therapy of a one-time initial loading dose of 600 mg, followed by 150 mg every day for six months, or standard Plavix therapy of 75 mg per day.

Of the patients whose PRU was below 230 and, therefore, not considered to have high platelet reactivity, 583 were randomly enrolled as clopidogrel responders treated with the standard clopidogrel regimen of 75 mg every day for six months.

While the varied cutoff values between the different platelet tests are seen as a source of confusion, they importantly identify patients at increased risk of ischemic events such as stent thrombosis after PCI and could be used to tailor therapy. “Different cutoff points may be necessary for the different devices because the tests all study platelet function in a different way,” Price says.

Yes, the consensus document referenced earlier stated that this very lack of standardization in cutoff values hinders the widespread adoption of these tests.

“A lot more work is needed to seek standardization because of the plethora of assays available,” Paré says. “Fortunately, various trials being conducted right now involving large numbers of patients, such as GRAVITAS, will serve to inform the field.”     

Getting the dose right

Additionally, standardizing loading dosing strategies will be integral to more widespread acceptance. “Increasing maintenance dose of clopidogrel [as in GRAVITAS] overcomes high platelet reactivity in a significant number of patients, but it is not effective 100 percent of the time,” Gurbel says.

In fact, a study presented at ESC.10 by Mehta et al showed that the use of a seven-day, double dose of clopidogrel reduced cardiovascular events and stent thrombosis in patients with acute coronary syndromes (ACS) undergoing PCI, but resulted in higher bleeding rates.

However, Bonello et al did not observe any significant difference in any subgroup of patients, regarding complications or bleeding events in their study population. Bonello points out that therapy dose based on platelet monitoring is “completely different” than a carte blanche dose increase.

“A simple dose increase could still be insufficient in some patients, and too much dose in others. Therefore, if you don’t use platelet reactivity to monitor the response of clopidogrel, and the dose is increased across the board, you could end up with more bleeds,” Bonello says.

Is this really necessary?

Also presented at ESC.10 were substudy analyses by Paré et al of the CURE and ACTIVE A trials, which found that the effect of clopidogrel compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status among the respective ACS and atrial fibrillation (AF) patient populations. The researchers hypothesized that the benefits of clopidogrel compared with placebo would be decreased in persons who carry a loss-of-function CYP2C19 allele and increased in carriers of the gain-of-function *17 allele, and, therefore, examined the efficacy and safety of clopidogrel compared with placebo according to genotype status among patients in the two randomized trials.

Paré et al concluded that CYP2C19 loss-of-function variants do not modify the efficacy and safety of clopidogrel. “Therefore, loss-of-function allele carrier status should not preclude the use of clopidogrel at currently recommended doses in patients with ACS whose condition is being managed conservatively.”

“Based on these findings in two very different patient populations, there is no reason to worry about genetic variants having adverse effects on clopidogrel treatment,” Paré says. “In these patient subsets, physicians can confidently continue treatment.” He adds the clopidogrel has been studied “very extensively and shown to be beneficial in patients with a strong safety profile.”

However, Price suggests that the findings of the ACTIVE A and CURE data are dependent on the specific patient populations in those trials. The data are “consistent with previous data that the risk of carriers of a loss-of-function CYP2C19 allele (including the *2 and *3 alleles) in clopidogrel-treated patients depends upon the clinical and procedural risk. The strongest evidence of an association between poor metabolizers and patient outcomes is in those patients undergoing PCI for ACS.” He points out that ACTIVE A was an AF patient population, and the ACS patients in CURE were mainly treated with optimal medical therapy, not PCI. In contrast, Price points to the PLATO Genomics trial population as a more appropriate patient population to assess the clinical impact of carrier status.

New drugs=No need to test?

Two newer antiplatelet agents—prasugrel and ticagrelor (Brilinta, AstraZeneca)—have the potential to overcome the reduction in effectiveness of clopidogrel in carriers of two loss-of-function alleles because the newer drugs are not affected by loss-of-function polymorphisms. Also, Gurbel says that elinogrel (Novartis Pharmaceuticals), a reversible P2Y12 ADP receptor antagonist about to begin a phase III trial, shows promise and may be associated with less bleeding.

However, Bonello doesn’t see newer drugs as a reason not to individualize therapy. “With prasugrel and ticagrelor, we still need to guide therapy because it will allow clinicians to predict thrombotic events and, even more importantly, bleeding events that are more frequent because we will have very low platelet reactivity with these drugs,” he says. “There will still be room for platelet reactivity testing, but not genetic testing, as these drugs are not affected by loss-of-function polymorphisms.”

While both prasugrel and ticagrelor inhibit the P2Y12 receptor, Price questions whether these drugs should be administered in a widespread population, regardless of genotype status. “Ultimately, does uniform and potent inhibition of the P2Y12 receptor abrogate the need to understand your patient’s genotype and/or clopidogrel-induced platelet function?” he asks. “Or does an individualized approach based on phenotype of platelet function or genotype of CYP2C19 alleles provide overall net clinical benefit?

“The variable response to clopidogrel has yet to be explained either through genetics or clinical characteristics,” Price concludes. “Therefore, we may in the future discover new genetic markers of clopidogrel response and targets for individualized therapy.”