Variability and persistence of aspirin response in lower extremity peripheral arterial disease patients

Abstract

Objective To determine the prevalence of poor response to aspirin (ASA) therapy over 12-month follow-up in patients with lower extremity peripheral arterial disease (PAD), and to compare the classification agreement among different ASA response assays. Subjects Patients with PAD on ASA therapy at baseline were included from the ongoing Effect of Lipid Modification on Peripheral Arterial Disease after Endovascular Intervention Trial (ELIMIT), which is a randomized trial testing whether combination treatment with ezetimibe, niacin, and a statin will halt/regress atherosclerosis compared to statin monotherapy. Main Outcome Measures Patients who had baseline platelet testing and repeat testing at 6-month or 12-month follow-up were included. ASA responsiveness was tested using three different assays: Optical aggregation with 0.5-mg/mL of arachidonic acid (AA), optical aggregation with 10-μM of adenosine diphosphate (ADP), and platelet function analyzer-100 (PFA-100) testing with collagen/Epinephrine (Epi) loaded cartridges. ASA response was defined as AA aggregation <30%, ADP aggregation <70%, or PFA-100 Epi> 164 sec. Patients who showed response to ASA at baseline were classified as Responders. Poor response to ASA was defined as AA aggregation ≥30%, ADP aggregation ≥70%, or PFA-100 Epi ≤164 sec. Patients who showed poor response (PR) to an assay at baseline, but then were responsive at follow-up visits were classified as Initial PRs. Patients who showed poor response at baseline and all follow-up visits were classified as Persistent PRs. The classification agreement between assays was tested using the kappa statistic. Results Of 102 patients randomized in ELIMIT, 80 patients satisfied inclusion criteria. There were no significant baseline demographic differences between Responders, Initial PRs, and Persistent PRs. The prevalence of persistent poor response varied by the assay used; 5% of subjects (4/80) were Persistent PRs by AA aggregation, compared to 27.5% (22/80) of subjects by ADP aggregation, and 9.9% (7/71) of patients by PFA-100 Epi. Regarding the agreement of the assays, only AA aggregation and PFA-100 Epi agreed significantly (K=0.3223; 95% CI 0.15–0.493, P=0.0001), and though statistically significant, the magnitude of this agreement is small. AA aggregation and ADP aggregation did not agree (K=0.1161; 95% CI −0.004–0.236, P=0.029), nor did ADP aggregation and PFA-100 Epi (K=0.0044; 95% CI −.151–0.160, P=0.48). Conclusions Between 5–27.5% of PAD patients were Persistent PRs to ASA over 6–12-month follow-up using different platelet assays. Further, these commonly used platelet assays show weak agreement in determining poor response to aspirin.

Multi-parameter assessment of platelet inhibition and its stability during aspirin and clopidogrel therapy

“…Consistent with our findings, these studies also showed that stability varies with assays employed to measure platelet response [22–25]. In a study that assessed platelet function in patients with lower extremity peripheral arterial disease (PAD) on aspirin at baseline, 6 months and 1 year, a poor to moderate degree of correlation and agreement was found between the repetitive measurements of LTA-AA and LTA-ADP [22]. Similarly, comparisons of baseline and 1 year platelet function profiles in patients with a recent transient ischemic attack (TIA) or ischemic stroke on aspirin revealed a poor correlation and poor to moderate agreement for Verify Now ® Aspirin, LTA-AA, and LTA-ADP assays [23].…”

“…Consistent with our findings, these studies also showed that stability varies with assays employed to measure platelet response [22–25]. In a study that assessed platelet function in patients with lower extremity peripheral arterial disease (PAD) on aspirin at baseline, 6 months and 1 year, a poor to moderate degree of correlation and agreement was found between the repetitive measurements of LTA-AA and LTA-ADP [22].…”

Association between cell-derived microparticles and adverse events in patients with nonpulsatile left ventricular assist devices

“…Platelet-leukocyte aggregates were identified by detecting CD41 staining in cells gated for CD11b positivity, and platelets bound with von Willebrand factor were identified by detecting CD41 staining in cells gated for von Willebrand positivity, as previously described. 26 …”

“…26 Platelet turnover was measured by quantifying the number of reticulated platelets, as previously reported. 27 Briefly, 5 μl of citrated whole blood was added to Isoflow solution (Beckman Coulter, Miami, FL), either alone (control tube) or with 100 μl of Retic-COUNT reagent (BD Retic-COUNT Kit, BD Biosciences, San Jose, CA).…”

PFA ‐100‐measured aspirin resistance is the predominant risk factor for hospitalized cardiovascular events in aspirin‐treated patients: A 5‐year cohort study

“…There are several clinical methods for evaluating aspirin resistance. Although the effect of aspirin on thromboembolic inhibition is complicated, each method for aspirin resistance offers clinically relevant data . Despite the lack of a standard laboratory method for assessing aspirin resistance, the PFA‐100 system is a well‐documented, convenient and quick instrumental method for screening platelet function .…”