For patients who undergo nonemergent percutaneous coronary intervention (PCI), tailoring the loading dose of clopidogrel according to platelet reactivity reduced the rate of early stent thrombosis, according to findings from a new trial. Individualized dosing also reduced the incidence of major adverse cardiovascular events (MACE) without increasing bleeding events.

Franck Paganelli, MD, Hôpital Université Nord, Marseilles, France, reported findings from the Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Prevent Stent Thrombosis study at the American Heart Association Scientific Sessions meeting in New Orleans.

Clopidogrel resistance has been linked to increased adverse events in patients who are undergoing PCI. Dr. Paganelli and colleagues have been exploring the role of the vasodilator-stimulated phosphoprotein (VASP) index, a measure of platelet reactivity that is specific to the P2Y₁₂ receptor, to guide clopidogrel dosing. The present study examines whether additional loading doses of clopidogrel, based on the VASP index, can overcome problems that are related to clopidogrel resistance, including stent thrombosis and MACE, which have been shown to occur more frequently in patients with elevated platelet reactivity (elevated VASP index).

The trial included 429 “low responders” to clopidogrel, whose VASP index remained ≥50% (elevated platelet reactivity) after an initial loading dose of clopidogrel 600 mg. These patients were randomly assigned to additional VASP-guided clopidogrel dosing, with the goal of achieving a VASP index <50% (low platelet reactivity) prior to PCI (n=214), or PCI without additional clopidogrel dosing (n=215). In the VASP-guided arm, up to 3 additional loading doses of 600 mg of clopidogrel (maximum clopidogrel dose 2400 mg) were administered before PCI.

After the second clopidogrel dose in the VASP-guided group, 132 patients (61%) had a low VASP index of <50% and proceeded to PCI. Of the remaining patients, 83 (38%) required third doses and 40 (18%) required fourth doses of clopidogrel prior to intervention. The latter group included 17 patients (8%) whose VASP index remained elevated (>50%) despite a total of 2400 mg of clopidogrel. The primary endpoint was the rate of early definite stent thrombosis.

During the first 30 days after PCI, 1 patient in the VASP-guided group and 10 patients in the control group experienced stent thrombosis (p<0.01). All thrombotic events occurred within the first 7 days of the 30-day observational period (Figure 1).

Tailored clopidogrel dosing also reduced the secondary endpoint of MACE in the VASP-guided group (0.5%) compared with the control group (8.9%; p<0.001). These results included a reduction in myocardial infarction (0.5% vs 4.8%; p=0.01), trends toward fewer cardiovascular deaths (0% vs 1.8%; p=0.06), and urgent revascularizations (0% vs 2.3%; p=0.06).

Increasing clopidogrel dosing up to 2400 mg prior to PCI did not appear to increase bleeding risk. No differences were observed between the VASP-guided and control groups in all TIMI bleeding (3.7% vs 2.8%; p=0.8), major bleeding (0.9% vs 0.9%; p=1.0), or minor bleeding (2.8% vs 1.9%; p=0.8; Figure 2).

“Trying to identify the optimal loading dose using a laboratory test is a very creative idea,” said Elliott Antman, MD, Brigham and Women's Hospital, Boston, MA. Dr. Antman cautioned that giving iterative loading doses of clopidogrel based on VASP index results takes time, up to 3 days in patients who require third and fourth clopidogrel loading doses. “You need time for the loading dose to exhibit its effect, and then you need time for the laboratory result to come back,” because bedside testing currently is not available, he said.

Future alternatives to clopidogrel therapy, such as prasugrel, AZD 6140, and cangrelor, may provide simpler dosing that is not susceptible to wide variations in treatment response, Dr. Antman said.