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 [mailto:apalmer@perfuse.org]

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.