Platelets play a major role in
thrombus formation, as well as in the pathogenesis of
atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all
vascular diseases, since
thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although
acetylsalicylic acid (
aspirin) has been shown to reduce the incidence of
myocardial infarction and
stroke, its effect is weak and more effective
antithrombotic agents are required to manage patients at high-risk for recurrent vascular events.
Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive
proteins,
fibrinogen and
von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial
thrombosis in
acute coronary syndromes (
unstable angina and
non-ST-elevation myocardial infarction) and
percutaneous coronary interventions (PCI) such as balloon dilatation and
stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and
secondary prevention of
thrombosis as chronic treatment, especially in high-risk patients.
Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral
platelet inhibitors for ischaemic conditions including
unstable angina, restenosis after PCI and
stroke.
Lotrafiban is converted from an esterified
prodrug by plasma and liver
esterases to a
peptidomimetic of the
arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of
fibrinogen and
von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that
lotrafiban is clinically safe and well-tolerated in patients with recent
myocardial infarction,
unstable angina, transient ischaemic attack (TIA), or
stroke when added to
aspirin therapy. With
lotrafiban, a worldwide large-scale Phase III clinical trial
BRAVO (blockage of the GPIIb/IIIa receptor to avoid vascular occlusion) is currently underway. In general, GPIIb/IIIa blockade seems clinically very promising. A number of unresolved issues, however, remain to be elucidated.