Un-POPULAR? Utility of platelet-function tests “modest”

Nieuwegein, the Netherlands – The first head-to-head comparison of different platelet-function tests, which gauge the antiplatelet efficacy of clopidogrel, shows that just three of the six assays evaluated were able to predict the likelihood of an adverse cardiovascular event in patients undergoing elective PCI with stent implantation.

But importantly, the predictive values of these three tests were only modest in the study, called POPULAR, and therefore the results do not support the routine use of such platelet-function tests to guide clinical practice in this low-risk population of patients, say Dr Nicoline J Breet (St Antonius Hospital, Nieuwegein, the Netherlands) and colleagues in the February 24, 2010 issue of the Journal of the American Medical Association.

The POPULAR study findings were first presented at the AHA meeting last November, and second author Dr Jochem W van Werkum (St Antonius Hospital) told heartwire: “We still believe the predictive value of these tests is good,” but statistical analyses performed since then illustrate that, when added to conventional clinical risk factors or procedural risk factors, the areas under the curve (AUC) for the three tests are “always moderate”; hence, “we changed the nuance of the conclusion a little bit.”

Such tests may be prove more useful in higher-risk patients, such as those with acute coronary syndrome or in ST-elevation-MI patients, van Werkum added, “and there are some studies that demonstrate that platelet-function testing is very promising in those categories of patients,” he says. However, for definitive proof, “We will have to await the results of ongoing trials,” he noted.

But there is one exception—the Dutch doctors are already using platelet-function tests in patients coming to their stent-thrombosis outpatient clinic, van Werkum explained. “We run platelet-function tests, do some genetic testing, and we perform optical coherence tomography to look at whether the stent is malappositioned. We make sure because we know patients with stent thrombosis are at extremely high risk [of adverse events].”

Newer platelet-function tests not included in POPULAR

Around a third of all patients are believed to have a reduced response to clopidogrel, leaving them at higher risk of cardiovascular events if they are taking normal doses of the drug. High platelet reactivity despite clopidogrel treatment is associated with increased thrombotic events—hence the evolution of platelet-function tests. POPULAR is the first large trial to compare just how well different tests do at predicting CV events and whether the findings are comparable across tests.

The study was conducted in a single center in 1069 consecutive patients taking clopidogrel and undergoing elective PCI and stent implantation between December 2005 and December 2007.

On-treatment platelet reactivity was measured by:

Light transmittance aggregometry (with ADP 5 µmol/L and 20 µmol/L as the agonist).
The VerifyNow P2Y12 assay (Accumetrics, San Diego, CA).
The Plateletworks assay (Helena Laboratories, Beaumont, TX).
The IMPACT-R assay (with and without ADP; Matis Medical, Beersel, Belgium).
The DADE PFA collagen/ADP test cartridge (PFA-100 system, Siemens Healthcare Diagnostics Products, Marburg, Germany).
Halfway through the study, the final prototype of a novel test, also by Siemens, the Innovance PFA p2Y PFA-100 system, became available for inclusion.

(The paper lists these six tests, but in the heartwire report of the POPULAR study from the AHA 2009 meeting, eight tests were noted because the two versions of the light-transmittance-aggregometry test and the IMPACT-R test were listed separately.)

The patients received three different but adequate clopidogrel dosing strategies, Breet et al note, adding that this may represent a limitation, in that previous studies have shown differences in the effect of platelet reactivity of these three dosing regimens. “However, these three regimens are current clinical practices, and our study therefore reflects the clinical relevance of monitoring platelet function in daily practice,” they observe.

They also point out that other, newer platelet-function tests—such as the Multiplate (Dynabyte Informationssysteme, Munich), the thromboelastograph, and the flow-cytometric-vasodilator-stimulated phosphoprotein (VASP) assay—were not available at the time they began POPULAR or were considered too preliminary to include.

Three best tests have only modest ability to predict a primary event

Only three of the tests examined—light transmittance aggregometry, VerifyNow, and the Plateletworks assay—were significantly associated with the primary end point of the study, a composite of death, MI, stent thrombosis, and stroke at one year.

“I think one of the most interesting messages here is that the aggregation-based tests seem to predict best and the shear-based tests don’t predict well,” van Werkum noted.

He said the Innovance system (Siemens) also showed some promise in predicting the primary end point, but because it was adopted only halfway through the study, the sample size of patients who received this test was too small to have sufficient power to detect any relationship.

And even for the three best tests, the AUC showed only “modest ability” for discriminating between patients having and not having a primary event, ranging from 0.61 to 0.63 only, said van Werkum.

Another message: None of the tests predicted bleeding events

Van Werkum also pointed out another important finding of the study, also highlighted at the AHA meeting: the fact that none of the assays studied in POPULAR were able to predict those patients at higher risk of bleeding following stent implantation: “It’s important to mention this, as this is a message too,” he notes.

It is hoped that the situation with regard to when to use these platelet-function tests and how to alter therapy in response to their findings will become a lot clearer once the results of the GRAVITAS and TRIGGER PCI trials are known, van Werkum concluded.

TRIGGER PCI is assessing the efficacy of prasugrel vs clopidogrel for the reduction of adverse cardiovascular outcomes in patients with coronary artery disease undergoing PCI with at least one drug-eluting stent (DES) who have reduced responsiveness to clopidogrel, using the VerifyNow test. GRAVITAS is looking at whether intensifying clopidogrel treatment in those with reduced responsiveness to clopidogrel, also based on VerifyNow, will result in lower cardiovascular event rates in patients with stable angina or ischemia, unstable angina without ST changes, or NSTE-ACS receiving a DES.