Tailored clopidogrel dosing cuts stent thrombosis after PCI

19 November 2008

MedWire News: A tailored approach to clopidogrel treatment reduces stent thrombosis and major cardiac events without increasing bleeding in patients undergoing percutaneous coronary intervention (PCI), results of a large randomized controlled trial indicate.

The study authors say their results may represent a “paradigm shift” by demonstrating a therapeutic window for antiplatelet therapy in PCI patients and supporting a clinical benefit of platelet reactivity monitoring.

The study, titled “Tailored clopidogrel loading dose according to platelet reactivity monitoring decrease early stent thrombosis,” was presented by Frank Paganelli (Hôpital Universitaire Nord, Marseille, France) at the American Heart Association 2008 Scientific Sessions held in New Orleans, Louisiana, USA.

Paganelli began by explaining that there is a large inter-individual variability in the response to clopidogrel, even with very large loading doses. Recently, a platelet assay known as the vasodilator-associated stimulated phosphoprotein (VASP) index has been developed. A VASP index ≥50% is considered the optimum threshold for identifying clopidogrel-resistant patients who are at increased risk for thrombotic events.

In this study, Paganelli’s team hypothesized that lowering the VASP index among clopidogrel poor-responders due to undergo PCI would reduce the rate of stent thrombosis.

They began by screening 1122 PCI candidates, 429 of whom had a VASP index ≥50% in response to an initial loading dose of aspirin 250 mg and clopidogrel 600 mg. This subset was randomly assigned to receive PCI with standard maintenance dosing (aspirin 160 mg plus clopidogrel 75 mg) or to VASP-guided clopidogrel loading, with PCI not performed until the VASP index was <50%.

In the VASP-guided group, 70% of patients had a VASP index <50% after two loading doses of clopidogrel. But 8% of patients remained above this threshold even after four loading doses, equivalent to 2400 mg of clopidogrel. These are true clopidogrel-resistant individuals, said Paganelli.

The primary endpoint was definite stent thrombosis at 30 days post-PCI. This was significantly reduced in the VASP-guided group as compared with controls (0.5% vs 4.7%). All stent thromboses occurred in the first 7 days, Paganelli noted.

Several other endpoints significantly favored VASP-guided therapy versus control. These included rates of subacute stent thrombosis (0.5% vs 3.7%), myocardial infarction (0.5% vs 4.8%), and major adverse cardiac events (0.5% vs 8.9%). There were also nonsignificant trends toward reduced cardiovascular death and reduced repeat revascularizations in the VASP-guided group.

Reassuringly, rates of minor bleeding, major bleeding, and any bleeding were similar between the two study arms.

Paganelli concluded: “Adjusting the clopidogrel loading dose according to platelet-reactivity monitoring decreases the rate of stent thrombosis at 30 days in patients with clopidogrel low-response without increasing bleeding.”

He suggested that patients could be divided into three groups according to their VASP index: Good responders (VASP <50% after a first bolus of clopidogrel 600 mg); low responders (VASP >50% after the first bolus but sensitized after up to three additional loading doses); and resistant patients (VASP >50% despite up to 2400 mg of clopidogrel).

American Heart Association Scientific Sessions; New Orleans, Louisiana, USA: 8–12 Nov 2008