How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification

Abstract

The inhibitory platelet effect of clopidogrel is insufficient in approximately 5 to 30% of patients. These low responders (LR) face a significantly higher risk of cardiovascular complications. The therapeutic management of LR is still undefined. In the present study, we evaluate a novel therapeutic algorithm to reduce the incidence of clopidogrel resistance. One hundred sixty-one patients on 100 mg of aspirin co-medication underwent elective coronary stenting and were given an initial dosage of 600 mg clopidogrel, followed by 75 mg clopidogrel daily. 48 h later, the platelet responsiveness was tested with ADP (5-20 microM) stimulation by impedance aggregometry (Chronolog 590). A significant rise in impedance (>5 Omega after 6 minutes, aggregation index >65%) was defined as LR. In this subgroup, platelets were stimulated with the selective P2Y(12)-ADP receptor antagonist 2-MeS-AMP. One hundred twenty-three patients were clopidogrel-responders (76.4%) and 38 patients were LR (23.6%). A defect of the ADP-receptor P2Y(12) was found in three out of 38 LR (7.9%). Inhibition of platelet aggregation indicating clopidogrel-responsiveness was achieved with either a clopidogrel high-dose regimen (22/38, 57.9%); a repeat loading dose, doubling the maintenance dose) or with an alternative therapy with ticlopidine (8/38 (21.1%); 250 mg twice daily). Thus the incidence of LR was reduced from 23.6% to 5.0%. Our aggregometer-guided therapeutic algorithm reduced the relative percentage of clopidogrel LR by 78.9%. This approach could prove to be helpful in achieving a further decrease in the incidence of clopidogrel resistance.

Clinical importance of aspirin and clopidogrel resistance

“…In multivariate analysis, higher angina class was independently associated with lower inhibition of platelet aggregation (P = 0.018) Buonamici et al [97] Optical aggregometry Ticlopidine could be an alternative agent in the treatment of clopidogrel resistance as previous studies have suggested [112,113] . A recent case report presented three patients with acute stent thrombosis showing biological non-responsiveness to clopidogrel, despite overdosing to 150 mg/d and a sufficient duration of the treatment.…”

The Potential Value of Near Patient Platelet Function Testing in PCI: Randomised Comparison of 600 mg versus 900 mg Clopidogrel Loading Doses

“…There is now evidence that repeated loading doses [19]; increased maintenance doses of clopidogrel [19, 20]; and changing to Ticlopidine [19] or Prasugrel [21] improve the observed antiplatelet response and can decrease the rate of poor responders to clopidogrel by 60 [20] to 78.9% [19] but as yet little direct evidence that these strategies improve clinical outcomes post PCI. However, recently Bonello et al, using a strategy of VASP guided clopidogrel loading prior to PCI with up to 3 further 600 mg clopidogrel loading doses administered to obtain adequate response did, in addition to improving response to clopidogrel, achieve significantly improved MACE rates at 30 days without increased bleeding [22].…”

Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea

“…As previously described,14,15 impedance aggregometry and outcomes in the form of platelet aggregation in whole blood samples were examined by an impedance aggregometer (Model 590; Chrono-Log Corp., Havertown, PA, USA) and analyzed by the AggroLink software package (Chrono-Log Corp.). Blood samples were collected for platelet aggregation 9 days after pantoprazole or ranitidine treatment.…”

“…Aggregation of platelet was measured in terms with the change in impedance (Ω) from start to finish after 6 minutes. Based on the previous studies, an impedance ≤5 Ω was defined as a normal response to clopidogrel treatment, while an impedance >5 Ω was defined as clopidogrel low-response (CLR) 14,15. The outcomes measured by Chrono-Log 590 aggregometer showed reproducibility with a variability of 10%.…”