High Platelet Reactivity Linked to More Adverse Events After Endovascular Procedures

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In patients undergoing peripheral endovascular procedures, high on-treatment platelet reactivity is associated with a dramatic increase in risk of adverse clinical events, according to a study published online April 24, 2013, ahead of print in the Journal of the American College of Cardiology. In order to tailor antiplatelet therapy, point of care clopidogrel assessment might be appropriate in selected patients, the authors suggest.

For the PRECLOP (Platelet Responsiveness to CLOpidogrel treatment after Peripheral endovascular procedures) study, researchers led by Stavros Spiliopoulos, MD, PhD, of Patras University Hospital (Rio, Greece), looked at 100 consecutive patients with femoropopliteal peripheral arterial disease (PAD) scheduled for infrainguinal angioplasty or stenting who underwent platelet function testing using the VerifyNow P2Y12 point-of-care assay (Accumetrics, San Diego, CA). Subjects, who were diagnosed with either Rutherford stage 3 intermittent claudication or Rutherford stage 4-6 CLI, were stratified into quartiles by P2Y12 reaction units (PRU).

Cutoff Established

At 1 year, the overall cumulative event rates (composite of death, bleeding, major amputation, or clinically driven TVR)—the primary endpoint—were 4% in the first (lowest) PRU quartile, 12% in the second, 52% in the third, and 84% in the fourth (highest). Pairwise comparisons found differences in the composite endpoint between all quartiles (P < 0.05 for all) except for the first vs. second quartiles.

ROC analysis found the optimal cut-off value to be a PRU of 234 or greater for the composite endpoint (AUC 0.883; 95% CI 0.811-0.954; P < 0.0001) with a sensitivity of 92.1%, specificity of 84.2%, positive predictive value of 67.3%, and negative predictive value of 93.9%.

In addition, subgroup analysis showed that CLI (P < 0.0001), chronic renal disease (P = 0.002), and diabetes (P = 0.004) were related with increased rates of high on-treatment platelet reactivity. Still, multivariable analysis determined that high on-treatment platelet reactivity was the only independent predictor of adverse events (HR 16.9; 95% CI 5-55; P < 0.0001).

Overall, 38 adverse clinical events (composite of death, major stroke, major amputation, TVR, and bypass) were reported. The majority of events were TVR (94.7%), with a single major amputation and 1 death due to major ischemic stroke in patients with PRU values of 339 and 414, respectively, making up the rest.

None of the events occurred within 30 days of the procedure, and the majority of TVR events occurred due to re-occlusion of the target vessel (61.1%). In about one-third of the femoropopliteal TVR cases (30.5%), additional below-the-knee interventions were performed to improve run-off, with bleeding events requiring additional intervention occurring in 4.0% of patients.

A New Tool to Tailor Treatment

“This study demonstrated that an inadequate response to clopidogrel, identified using point of care testing just prior to the procedure, is a new strong independent predictor of reduced event-free survival, adversely influencing mid-term clinical outcomes of peripheral angioplasty and stenting,” Dr. Spiliopoulos and colleagues write.

They advocate the use of such testing to detect high on-treatment platelet reactivity during clopidogrel treatment so as to “recognize patients at higher risk for clinical adverse events and to encourage individualized, alternative, antiplatelet regimens such as double clopidogrel dose, or newer antiplatelet drugs such as prasugrel or ticagrelor, with the aim to improve clinical outcomes after peripheral endovascular procedures.”

In an e-mail communication, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), told TCTMD that PRECLOP is a “provocative study.” Of note, he wrote, “the cutoff value of ≥ 234 PRU is slightly higher than the cutoff value proposed for coronary stent thrombosis (> 208 PRU) as demonstrated in ADAPT-DES . . . and the HR associated with ≥ 234 PRU for 1 year ischemic event occurrence in PAD patients is significantly higher compared to 1 year stent thrombosis in the ADAPT-DES study (16.9 vs. 2.49).”

This indicates that ischemic events in these patients “are highly platelet-centric,” according to Dr. Gurbel. “PAD patients with high PRUs on clopidogrel therapy may be suitable candidates for either ticagrelor or prasugrel for long-term therapy. However, large-scale studies will be needed to validate the utility of more potent P2Y12 inhibitors in patients with PAD undergoing revascularization,” he added.

Study Details

The majority of patients (71%) were men and the mean age was 68.5 years. Significantly more diabetic patients were included in the third vs. the first quartile and more smokers were included in the fourth vs. first quartile. Most of the treated lesions were classified as TASC II A, but TASC II classification of the lesions was similar among all quartiles.

Dual antiplatelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) was prescribed for 6 months following the procedure, while single antiplatelet therapy with clopidogrel only (75 mg/day) was continued throughout the remainder of the follow-up period.



Spiliopoulos S, Pastromas G, Katsanos K, et al. Platelet responsiveness to clopidogrel treatment after peripheral endovascular procedures - The PRECLOP study: Clinical impact and optimal cut-off value of high on treatment platelet reactivity. J Am Coll Cardiol. 2013;Epub ahead of print.



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  • Dr. Spiliopoulos reports no relevant conflicts of interest.
  • Dr. Gurbel reports associations with several pharmaceutical companies.