High Platelet Reactivity Predicts Poor Outcomes, Routine Testing Still Debated

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Zeroing in on the population of patients who may stand to benefit from platelet function testing, a new meta-analysis shows that high-risk subjects who are poor responders to clopidogrel after percutaneous coronary intervention (PCI) suffer worse long-term cardiovascular events. But the study, which appears in the November 1, 2011, issue of the Journal of the American College of Cardiology, leaves open the issue of whether such testing should be routine.

George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY), and colleagues looked at patient-level data from 6 studies totaling 3,059 patients tested for clopidogrel responsiveness following PCI using the VerifyNow P2Y12 (Accumetrics, San Diego, CA) assay. Patients were analyzed according to P2Y12 reaction unit (PRU) quartiles:

• Quartile 1: less than 138 PRU
• Quartile 2: 138 to 200 PRU
• Quartile 3: 201 to 258 PRU
• Quartile 4: more than 258 PRU

Median PRU values by quartile were 92, 172, 229, and 294, respectively (P < 0.001). Patients in quartiles 1 and 2 showed similar levels of the primary composite endpoint (death, MI, and stent thrombosis) at 2 years, while quartiles 3 and 4 were significantly higher for the composite as well as most of the component endpoints (table 1).

Table 1. Event Rates by PRU Quartile

^a P = 0.02 vs. Quartile 1.
^b P < 0.001 vs. Quartile 1.
^c P = 0.007 vs. Quartile 1.
^d P = 0.002 vs. Quartile 1.

 

There was a 4% increase in the primary endpoint for every 10 unit increase in PRU (HR 1.04; 95% CI 1.03-1.06; P < 0.0001).

On receiver-operating characteristic curve analysis, the researchers determined an optimal cut-off value of 230 PRU with sensitivity, specificity, positive predictive, and negative predictive values of 55%, 65%, 11%, and 95%, respectively, for predicting the primary composite endpoint. Using the cut-off threshold, patients with high platelet reactivity (≥ 230 PRU) had a higher rate of death, MI, and stent thrombosis (14.7%) out to 2 years compared with patients with normal platelet reactivity (< 230 PRU; 7.0%; HR 2.10; 95% CI 1.62-2.73; P < 0.001). Patients above the PRU threshold also had higher rates of the component endpoints:

• Mortality: HR 1.66; 95% CI 1.03-2.68; P = 0.04
• MI: HR 2.04; 95% CI 1.51-2.76; P < 0.001
• Stent thrombosis: HR 3.11; 95% CI 1.50-6.46; P = 0.002

The PRU threshold was predictive of events in various subgroups defined by sex, age (cut-off of 65 years), and ACS status. The only subgroup in which the PRU threshold was not predictive were those with diabetes (P = 0.32 for primary endpoint).

The researchers conclude that “the level of on-treatment platelet reactivity according to the P2Y12 assay is associated with long-term cardiovascular events after [PCI].” However, they add, in the absence of data regarding how platelet function testing can guide treatment, “recommendations for routine testing are not possible.”

The Million Dollar Question

In a telephone interview with TCTMD, Dr. Dangas noted that the association between high platelet reactivity and CV events is fairly well established. “The million dollar questions is, how high is high?” he said. “We have documented that there are three levels of risk: a medium risk at around 200 PRU, the most meaningful cut-off at 230, and an extreme high-end cut-off at 260, which is the top quartile.”

To which populations these cut-offs apply is equally important. “We found that these were mostly outpatients at high risk or who had unstable disease,” Dr. Dangas said. “You cannot go and apply these cut-offs indiscriminately to any patients including stable patients, because then your event rates are going to be extremely low. GRAVITAS and TRIGGER PCI found out the hard way that their event rates were extremely low because they studied stable patients.”

GRAVITAS failed to find a benefit of high-dose clopidogrel in patients who were poor responders on the VerifyNow assay while TRIGGER PCI was stopped early due to low events. In the current meta-analysis, 35% of the patients had an acute coronary syndrome, 74% had hypertension, 64% had dyslipidemia, and 24% had diabetes.

Don’t Test, Don’t Know

Dr. Dangas did recommend that platelet function testing can be useful. “If you don’t test, you don’t know,” he said. “If you think by testing you’re going to identify a group with a high event rate, I think you have to look at the higher end of the PRU scale, over 260, and combine that with some significant clinical risk such as STEMI.”

And in the event that a high-risk patient with a high PRU value is identified, “I would use a therapy that has been proven to improve platelet activation inhibition such as prasugrel,” Dr. Dangas said. “This hasn’t been specifically tested prospectively, but it has indirectly. The TRITON-TIMI 38 study was positive in patients with ACS undergoing PCI [given prasugrel].”

But according to Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), such a testing and treatment strategy would be premature. “I completely agree that it would be logical to react to this study and say ‘obviously we should be testing everyone’s platelet reactivity,’ but other than being shown to be a powerful predictor of future events, the study doesn’t tell us what to do with that information,” he told TCTMD in a telephone interview.

Where Logic Ends

Dr. Bhatt stated that the concept of testing high-risk PCI patients with the option of giving poor clopidogrel responders prasugrel “is very logical and very scientific, but I hesitate to make that recommendation. Just because it’s logical doesn’t mean we don’t need to prove it, because logic sometimes ends up being disproved in medicine.”

Both Drs. Bhatt and Dangas agreed that what is needed is a GRAVITAS-like trial of tailoring antiplatelet therapy based on platelet function measurements, but in a high-risk patient population. “In fact, we in the physician community need to insist on that dataset before we start changing our practice patterns,” Dr. Bhatt said. “The problem is in too quickly embracing testing without adequate evidence to support it, potentially creating a situation where the testing becomes the standard of care without proving it works.”

At Mount Sinai, such testing is already in use in a limited capacity. “We test patients who are on previous clopidogrel therapy coming into the cath lab for repeat treatment,” Dr. Dangas said. “It’s a little difficult to test people who we’re giving clopidogrel to for the first time to see the immediate results due to the logistics of clinical practice.”

Economic Reality

In an editorial accompanying the study, Stephen D. Wiviott, MD, also of Brigham and Women’s Hospital, and Willibald Hochholzer, MD, of Herz-Zentrum Bad Krozingen (Bad Krozingen, Germany), inject a note of realism into the debate. “We would like to see studies funded and performed that adequately address the gap between achieved platelet function and clinical outcomes,” they write.

However, “we do not anticipate that the desired evidence will be available soon,” they add, noting that in the absence of such data, “We believe that future economic pressures may force an increase in the use of platelet function testing without the highest level of direct evidence.”

 

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Sources:
1. Brar SS, ten Berg J, Marcucci R, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: A collaborative meta-analysis of individual participant data. J Am Coll Cardiol. 2011;58:1945-1954.

2. Wiviott SD, Hochholzer W. On-clopidogrel platelet reactivity: A target in sight? J Am Coll Cardiol. 2011;58:1955-1957.

 

 

Related Stories:

• Increased Clopidogrel Fails to Overcome High Platelet Reactivity
• Poor Clopidogrel Response Predicts Mortality in PCI Patients
• GRAVITAS Published: No Benefit from High-Dose Clopidogrel in Poor Responders