Against the backdrop of wide variability in thrombotic risk and clopidogrel response in patients following percutaneous coronary intervention (PCI) as well as growing use of more potent antiplatelet agents in higher-risk groups, an expert panel from the European Society of Cardiology (ESC) has provided recommendations about when platelet function testing is and is not warranted in everyday practice.

The consensus statement, published online September 25, 2013, ahead of print in the European Heart Journal, cautions that residual platelet reactivity is only one piece of information that can be used to inform decision making and should not substitute for clinical assessment of individual patients’ thrombotic and bleeding risks.

The writing team, led by Dániel Aradi, MD, PhD, of Heart Center Balatonfüred (Balatonfüred, Hungary), observes that current ESC guidelines recommend prasugrel or ticagrelor for all PCI-treated STEMI and NSTE-ACS patients barring a contraindication, while ACCF/AHA/SCAI guidelines do not explicitly endorse 1 P2Y12 inhibitor over another for these patients.

The 2011 ESC guidelines on NSTE-ACS give platelet function testing a class IIb recommendation, stating that it should not be performed routinely but may be considered in selected cases when clopidogrel is used. Meanwhile, US guidelines sanction functional testing in patients at high risk for poor outcomes after PCI, noting that if results show high on-treatment reactivity, alternative agents may be prescribed.

VerifyNow, Multiplate the Favored Assays

Four assays have been shown to predict clinical outcomes in large numbers of patients—VerifyNow P2Y12 (Accumetrics, San Diego, CA), Multiplate (Roche Diagnostics; Rotkreuz, Switzerland), vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and light transmission aggregometry—though results of these tests show limited agreement. The authors favor the “more standardized, user-friendly” VerifyNow and Multiplate tests to minimize methodological errors and enable more reliable generalization of test results.

Optimal thresholds to define increased thrombotic risk may depend on the clinical situation and are still under investigation, but available evidence suggests cutoffs of 208 P2Y12 reaction units (PRU) for VerifyNow, 46 U with Multiplate, and 50% with the VASP assay.

Measurement of response to aspirin is unreliable and testing is not recommended, the paper states.

Numeous prospective observational studies have demonstrated that high on-treatment platelet reactivity is a strong independent predictor of ischemic events after PCI, especially in ACS patients, the authors say. However, they add, platelet reactivity is not only a measure of drug response but a global indicator of direct drug response and coexisting patient comorbidities that may interfere with platelet activation, such as advanced age and diabetes.

Options for High On-Treatment Reactivity

In stable patients after uncomplicated PCI, standard-dose clopidogrel should be preferred and platelet function testing is not recommended, the paper states. However, testing may be considered if the results might change the therapeutic strategy due to:

• Unexpected occurrence of definite stent thrombosis despite DAPT compliance
• Markedly elevated risk for stent thrombosis because of procedural or clinical features
• The likelihood that stent thrombosis would be catastrophic (ie, PCI of the last remaining vessel or the unprotected left main stem involving bifurcation)

In addition, testing may be considered in selected clopidogrel-pretreated ACS patients with a history of major spontaneous bleeding or at high risk for bleeding, or who are at low risk of thrombotic events.

The options for intensifying therapy to overcome high on-treatment reactivity include increasing the clopidogrel dose, switching to a new-generation P2Y12 inhibitor, or adding a third agent. Increasing aspirin beyond a low maintenance dose (≤ 100 mg) based on functional testing is not recommended, since it does not improve clinical efficacy and may increase the risk of GI bleeding, Dr. Aradi and colleagues write. The choice of P2Y12 inhibitor should factor in both the platelet function test results and the patient’s bleeding risk, they note.

In patients with a clear indication for oral anticoagulation after PCI, such as those with A-fib or a prosthetic heart valve, triple therapy should include standard-dose clopidogrel; functional testing to guide possible dose modification or a switch to prasugrel or ticagrelor is not recommended.

Can Testing Help Find a ‘Sweet Spot’?

Although evidence is growing for a link between low platelet reactivity and increased bleeding risk after PCI, strategies such as reducing the dose of prasugrel or ticagrelor, or switching back to clopidogrel in those originally prescribed a novel agent, based solely on platelet function test results are also not recommended.

Nonetheless, in patients who experience a major bleeding event and remain at increased risk for recurrent bleeding, testing may be considered to facilitate the optimal therapy during or after the bleeding episode.

Moreover, the paper observes, the concept of using platelet function testing to titrate a therapeutic window, or ‘sweet spot,’ of P2Y12 inhibition that would navigate safely between thrombotic and bleeding risks is appealing, though randomized studies are needed to validate the effectiveness of such a strategy.

Recommendation for Future Trials

The main reason for platelet testing’s current restricted role, the authors propose, is the lack of adequately sized positive randomized controlled studies to show an improvement in clinical outcomes when testing guides therapy. To provide functional testing the best chance of proving its worth, they suggest that future trials should:

• Be large multicenter studies that are realistically powered for ischemic endpoints
• Include patients at high risk for stent thrombosis
• Use potent P2Y12 inhibitors such as prasugrel or ticagrelor to intensify platelet inhibition rather than high-dose clopidogrel
• Test the clinical value of assays that were not used in previous studies

Another area for future research, the authors suggest, involves the potential for platelet function testing to minimize bleeding complications. This is especially important for the new potent P2Y12 inhibitors in low-risk ACS patients, the elderly, and those who need triple therapy.

Authors Well Qualified to Make Recommendations

“This [paper] summarizes where we stand on platelet function testing at this point in time and what we need to do to move the field forward,” Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), told TCTMD in a telephone interview.

“I think the [recommendations on when to test] in routine practice are helpful to clinicians because the authors are all experts in translational research related to measuring platelet function, genetics, and patient outcomes,” he said, pointing out that the same cannot be said of the writers of the current ACS and PCI guidelines.

“There are lots of data linking high platelet reactivity to outcomes,” Dr. Gurbel said, “but the [piece] we’re really missing is evidence from a large-scale study showing that altering therapy based on the results of platelet function tests does anything for the patient.” However, in line with the paper, Dr. Gurbel endorsed functional testing in select high-risk patients on clopidogrel, such as those at high risk for and “a lot to lose” from stent thrombosis.

While he found the 208 PRU threshold for thrombotic risk well supported by available data, Dr. Gurbel emphasized that stable patients may have a different cut point from ACS patients and that the optimal threshold for stent thrombosis risk likely varies with the time from PCI.

Overall, it is important to be aware that “in roughly 30% of patients clopidogrel is basically a placebo” because the drug is not adequately metabolized, Dr. Gurbel observed, asking, “How logical is it to send these patients home with just an antiplatelet effect from aspirin?’

In fact, Dr. Gurbel’s only dissent from the paper centered on the recommendation to prescribe only low-dose aspirin. Not only is the relation of bleeding risk to aspirin dose cited by the authors controversial, he asserted, but “aspirin has a dose-dependent effect on platelet inhibition that is not apparent in the standard assay, so the optimal dose remains a mystery.”

Source:

Aradi D, Storey RF, Komócsi A, et al. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J. 2013;Epub ahead of print.

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