Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy.

Clopidogrel responsiveness (CR) following a loading dose (LD) predicts thrombotic events after percutaneous coronary interventions (PCI). Some of the mechanisms involved in large inter-individual variability in CR may be varied. We therefore postulated that there may be an intra-individual variability in CR. Two hundred and one patients receiving long-term therapy with aspirin and clopidogrel after drug-eluting stents PCI were prospectively included in this monocentre study along with any patient re-admitted within 12 months post-PCI. Platelet reactivity (PR) inhibition was assessed by the vasodilator phosphoprotein (VASP) index following a 600 mg loading dose of clopidogrel on each admission to determine CR (VASP 1 during the first admission and VASP 2 during re-admission). DeltaVASP = VASP 2 –VASP 1 was used to study intra-individual variability in CR. We observed that the response to a 600 mg LD of clopidogrel was poorly correlated within an individual (kappa = 0.33; p < 0.001 (n = 201)). Although most patients had increased platelet inhibition at the time of readmission, 35.3% of patients exhibited a decreased platelet inhibition despite chronic clopidogrel therapy and a 600 mg reload. Quartiles analysis of DeltaVASP demonstrated that insulin-treated diabetes was associated with decreased CR over time (p = 0.03). In addition to the large inter-individual variability in clopidogrel responsiveness, there is large intra-individual variability. Decreased clopidogrel responsiveness despite long-term clopidogrel therapy could be a trigger for recurrent thrombotic events.

Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis.

Stent thrombosis remains a significant pitfall of percutaneous coronary intervention (PCI). A recent trial observed that an adjusted loading dose (LD) of clopidogrel according to platelet monitoring decreases the rate of major adverse cardiovascular events after PCI. We investigated if such a strategy of a tailored clopidogrel LD according to platelet reactivity monitoring could decrease the rate of stent thrombosis. This multicenter prospective randomized study included 429 patients with a low clopidogrel response after a 600-mg LD undergoing PCI. Patients were randomized to a control group (n = 214) and to a vasodilator-stimulated phosphoprotein (VASP)-guided group (n = 215). In the VASP-guided group, patients received up to 3 additional 600-mg LDs of clopidogrel to obtain a VASP index <50% before PCI. The primary end point was the rate of stent thrombosis at 1 month. Secondary end points were rates of major adverse cardiovascular events and bleeding. Patients in the 2 groups had a high body mass index and were often diabetic (control vs VASP-guided group 28 +/- 5.1 vs 27.9 +/- 4.7 kg/m(2), p = 0.8, and 39% vs 33%, p = 0.2, respectively). PCI was performed in most patients for acute coronary syndrome in the 2 groups (52.3% vs 50.7%, p = 0.8). Despite a 2,400-mg LD of clopidogrel, 8% of patients in the VASP-guided group remained low responders. The rate of stent thrombosis was significantly lower in the VASP-guided group (0.5% vs 4.2%, p <0.01). The rate of major adverse cardiovascular events was also higher in the control group (8.9% vs 0.5%, p <0.001). There was no difference in the rate of bleeding (2.8% vs 3.7%, p = 0.8). In conclusion, a tailored clopidogrel LD according to platelet reactivity monitoring decreases the rate of early stent thrombosis after PCI without increasing bleeding.