Die hemmende Wirkung von Clopidogrel auf die Aggregation humaner Thrombozyten

Platelets are major players in pathophysiology of cardiovascular
diseases in man and animals. Therefore, antiplatelet strategies are
an important element in human medicine (e.g., for prevention of
thrombotic events after vascular interventions). Current guidelines
recommend dual antiplatelet therapy with clopidogrel 75 mg qd and
acetylsalicylic acid 100mg qd in patients undergoing elective
coronary stent implantation. However, several studies demonstrated
a high interindividual variability in antiplatelet response to
clopidogrel with a significant impact on clinical outcome. For
instance, the EXCELSIOR study showed that patients with an
insufficient response to clopidogrel (defined as >14%
aggregation after stimulation with ADP 5 µM) after loading with
clopidogrel 600 mg had a 3-fold higher incidence of death and
non-fatal myocardial infarction within one year after elective
coronary stenting. Therefore, the current prospective study aimed
to investigate if high on-treatment platelet reactivity with a
standard dosing of clopidogrel can be overcome by an increased
dosing regimen. Antiplatelet effects of clopidogrel were assessed
by light transmission aggregometry (stimulation with ADP 5 µmol/L)
at day 1 after loading with clopidogrel 600 mg and subsequent
elective coronary stenting. Out of the 117 patients enrolled, 39
were identified having a residual platelet reactivity >14%.
These patients received an additional bolus of clopidogrel 300 mg
and an intensified maintenance dosing regimen of clopidogrel 150 mg
per day. Patients with residual platelet reactivity ≤14% were
treated according to the labelled standard dosing regimen of
clopidogrel (75 mg qd). Platelet reactivity was assessed 2 and 4
weeks after PCI. Data from 57 patients without any adjustment of
clopidogrel dose served as control. The intensified dosing regimen
of clopidogrel decreased residual platelet reactivity significantly
compared to baseline assessments despite a persisting substantial
inter-individual variability. Median platelet reactivity in the
group of patients with dose adaption was slightly but significantly
higher compared to patients with adequate initial response and
treatment with clopidogrel 75 mg qd throughout. These results were
confirmed by additional tests such as aggregometry with higher
concentrations of ADP (20 µM) and analysis of surface protein
expression of platelets. After increasing the dose of clopidogrel,
no dose-related increase in systemic exposure to parent clopidogrel
or the inactive metabolite carboxy-clopidogrel could be determined
which most likely can be attributed to the large variability in
pharmacokinetics of clopidogrel. The higher dose of clopidogrel 150
mg qd was not associated with any evidence of an increased
incidence of bleeding. However, the present study was not
sufficiently powered to detect differences with regards to safety.
In conclusion, selective dose adaptation of clopidogrel is a
feasible way to achieve a better platelet inhibition in patients
with insufficient response to clopidogrel. These findings open the
field for large scale clinical studies investigating the impact of
tailored and individualized antiplatetet therapy on clinical
outcome in patients undergoing percutaneous coronary interventions.