News:Adjusting Clopidogrel loading dose according to platelet reactivity monitoring is associated with a decreased rate of stent thrombosis and no increase in bleeding
November 10, 2008 By Alexandra M. Palmer 
AHA 08-New Orleans, Louisiana: Investigators from France report today that adjusting the loading dose (LD) of Clopidogrel according to platelet reactivity monitoring decreases the rate of stent thrombosis at 30 days without any increase in bleeding in patients with Clopidogrel low-response. The data were presented by Dr. Franck Paganelli at the American Heart Association’s scientific sessions 2008.
Prior studies have demonstrated that there is large inter-individual variability in response to Clopidogrel in coronary artery disease (CAD) patients. This variability is related to various factors, from genetic to clinic ones, making a patient’s response to Clopidogrel unpredictable. Previous studies have also demonstrated a link between Clopidogrel low-response and thrombotic events. The goal of this trial was to examine whether or not using platelet monitoring to tailor the Clopidogrel loading dose translates into a reduction in the rate of stent thrombosis in patients with Clopidogrel low-response. This was a randomized study that enrolled 1,122 patients with acute coronary syndrome (ACS) and stable angina undergoing non-emergent PCI. Clopidogrel low-response was defined as a vasodilator-stimulated phosphoprotein (VASP) index =50% after a Clopidogrel LD of 600 mg and 250 mg of acetylsalicylic acid (ASA). 429 patients underwent randomization to a control (n=215) and VASP-guided LD (n=214). The latter group received up to 3 additional loading doses of 600 mg every 25 hours until VASP was <50% before PCI. In addition, all patients received 160 mg ASA and 75 mg clopidogrel. The control and VASP-guided groups had similar baseline characteristics. The average age of the study population was 66 years and the average body mass index (BMI) was 28 kg/m2. More than half of the patients were male, current smokers, dyslipidemic and hypertensive. On average, participants had 1-2 treated vessels and 1-3 stents. The primary endpoint was the Academic Research Consortium (ARC) definition of definite stent thrombosis (DST). The secondary MACE endpoints included cardiovascular (CV) death, MI, and U-TVR TIMI major and minor bleeding at 30 days. The duration of follow-up was one month.
Compared to patients in the control group, the VASP-guided group was associated with fewer sub-acute stent thromboses (control group vs. VASP-guided group: 3.7% vs. 0.5%, p=0.02) and early DST (control group vs. VASP-guided group: 4.7% vs. group 0.5%, p=0.01). Two patients presented with recurrent sub-acute stent thrombosis (2 recurrences for each, 1 in the control group and 1 in the VASP-guided group). There was no significant difference in the number of patients who experienced acute stent thromboses (control group vs. VASP-guided group: 0.9% vs. 0%, p=0.25). All early stent thrombosis occurred during the first 7 days. GP IIb/IIIa inhibitors were used in half of patients presenting with early stent thrombosis.
The rate of all MACE was less in the VASP-guided arm (control group vs. VASP-guided group: 8.9% vs. 0.5%, p<0.001. Myocardial infarction was also more prevalent in the control arm (control group vs. VASP-guided group: 4.8% vs. 0.5%, p=0.01). There was no statistically significant difference in the rate of cardiovascular death (control group vs. VASP-guided group: 1.8% vs. 0%, p=0.06) and urgent revascularization (control group vs. VASP-guided group: 2.3% vs. 0%, p=0.06) between the two groups.
There was no difference in bleeding between the two groups: major bleeding (control group vs. VASP-guided group: 0.9% vs. 0.9%, p=1), minor bleeding (control group vs. VASP-guided group: 1.9% vs. 2.8%, p=0.8), all bleeding (control group vs. VASP-guided group: 2.8% vs. 3.7%, p=0.8). There was no intra-cerebral bleeding and no fatal bleeding. The majority of patients had PCI through the radial access (55.6%).
This study suggests that an adjusted LD of Clopidogrel according to platelet reactivity monitoring decreases the rate of stent thrombosis at 30 days in patients with Clopidogrel low-response without increasing bleedings. Patients could be divided in 3 groups according to VASP index: Good-responders (VASP<50 % after a first bolus of 600 mg of clopidogrel (55%)), Low-responders (VASP>50 % after the first bolus but could be sensitized with up-to three additional LD (37%)), Resistants (VASP>50 % despite up to 2400 mg of Clopidogrel (8%)).
These results support the need for platelet reactivity monitoring, as it is shown here to prevent ischemic events without increasing bleeding. However, since less than 20% of the study population was female, the results lose power when applied to women. Further investigation would include a larger female population as cardiovascular death is a leading cause of death for women too.
- L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg,
P Barragan, F Dignat-George, F Paganelli. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent stent thrombosis. As presented at AHA 2008.
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