Platelet Inhibition Flags 30-Day Stent Thrombosis Risk



SAN FRANCISCO – Platelet inhibition in response to adenosine diphosphate antagonists strongly predicted stent thrombosis within 30 days of implanting a drug-eluting stent in 8,575 patients on dual-antiplatelet therapy after percutaneous coronary intervention.

Both absolute and relative levels of platelet inhibition to ADP antagonists, as measured by the VerifyNow P2712 test, independently predicted early stent thrombosis, with a significant proportion of the thromboses associated with poor platelet response to clopidogrel, which inhibits the P2Y12 receptor, Dr. Gregg W. Stone and his associates reported.

The study assessed platelet function after dual-antiplatelet therapy loading using a suite of VerifyNow branded tests, and the findings may not be applicable to other tests. The tests assessed platelet reactivity to aspirin (VerifyNow Aspirin) and clopidogrel (VerifyNow P2Y12), and assessed overall platelet responsiveness (VerifyNow IIb/IIa).

The risk for stent thrombosis tripled in patients with P2Y12 reaction units (PRU) measuring greater than 208, which accounted for 50% of stent thromboses in a multivariable analysis, he said at Transcatheter Cardiovascular Therapeutics 2011, sponsored by the Cardiovascular Research Foundation.

The risk nearly tripled with a PRU of 230 or greater or with 11% or less inhibition of PY12, which accounted for 41% and 33% of stent thromboses, respectively.

Factors that were not predictive of 30-day risk of stent thrombosis included the baseline level of platelet P2Y12 response, platelet responsiveness to aspirin, and overall platelet responsiveness after dual-antiplatelet therapy loading, he said.

Giving agents that are more effective at inhibiting ADP-induced platelet activation to large patient populations should reduce the risk of 30-day stent thrombosis based on these findings, said Dr. Stone, director of cardiovascular research and education at New York-Presbyterian Hospital and professor of medicine at Columbia University, New York.

In that sense, the results of the ADAPT-DES study (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) support the results of two previous studies, the TRITON-TIMI (Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) 38 trial (N. Engl. J. Med. 2007;357:2001-15) and the PLATO (Platelet Inhibition and Patient Outcomes) study (N. Engl. J. Med. 2009;361:1045-57), he said.

On the other hand, the low rate of stent thrombosis – 0.46%, or only 39 in 30 days – and the modest sensitivity and specificity of platelet function testing suggest that testing platelet responsiveness to ADP antagonists probably isn’t helpful for clinical decision-making about preventing 30-day stent thrombosis in most patients, although the findings may be helpful on a population level.

Testing for a PRU greater than 208 was 74% sensitive and 57% specific, for an accuracy of 58%. Testing for a PRU of 230 or greater was 64% sensitive and 65% specific, for an accuracy of 65%. Testing for P2Y12 inhibition of 11% or less was 51% sensitive and 80% specific, for an accuracy of 80%.

Measuring platelet responsiveness to ADP antagonists was predictive in both diabetic and nondiabetic patients and in patients with acute coronary syndromes, but not in patients with stable coronary artery disease.

Thirty of the 39 stent thromboses occurred in the 4,347 patients with acute coronary syndromes. In this subgroup, a PRU greater than 208 or P2Y12 inhibition of 11% or less predicted a fourfold increased risk for 30-day stent thrombosis, and a PRU of 230 or greater predicted a tripling in risk. These tests flagged 60%, 44%, and 41% of 30-day stent thromboses, respectively, in patients with acute coronary syndromes.

In patients without acute coronary syndromes, the tests were not significantly associated with 30-day risk for stent thrombosis.

Dr. Stone suggested that the poor prognostic accuracy in patients without acute coronary syndromes and the low rate of stent thrombosis in this subgroup (only 9 of the 39 thromboses that occurred) may explain the negative results in two previous trials involving clopidogrel and platelet reactivity, the GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety) study (JAMA 2011;305:1097-1105) and the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study.

Although ADAPT-DES was a registry, "we tried to run it more like a randomized trial," Dr. Stone said. Eleven sites in the United States and Germany enrolled patients between January 2008 and September 2011 who underwent successful and uncomplicated PCI with an approved drug-eluting stent.

The ADAPT-DES study plans a 2-year follow-up to assess associations between platelet responsiveness testing and the risk of late or very late stent thrombosis.

The study was funded by the Cardiovascular Research Foundation, Accumetrics (which makes the VerifyNow tests), Boston Scientific, Abbott Vascular, Cordis, Biosensors, The Medicines Company, Daiichi Sankyo, Eli Lilly, and Volcano. Dr. Stone has received consulting fees and honoraria from Abbott Vascular, Boston Scientific, Medtronic, Volcano, The Medicines Company, Daiichi Sankyo, and Eli Lilly.

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