The discovery of
thrombolytic agents goes back to the 1930s, when it was shown that substances derived from bacteria (
streptokinase,
staphylokinase), tissue (fibrinokinase), urine (
urokinase) or bat saliva could activate the fibrinolytic system. The potential to treat arterial
thrombosis with
plasmin was recognized, but it was not until 1958 that its first use in acute
ischaemic stroke (AIS) was described. However, since computer tomography (CT) was not available until the mid 1970s, optimal selection of patients was not possible. Early studies with
streptokinase in AIS showed an increased risk of intracranial haemorrhage and lack of efficacy, which was associated with low
fibrin specificity. The search for new agents with a better risk-benefit profile continued until 1979 when
tissue plasminogen activator (t-PA) was discovered. In 1983 it became possible to produce recombinant t-PA (rt-PA) by expression of a cloned gene which enabled clinical trials to be started, mainly for coronary thrombolysis. In 1995, the National Institute of Neurological Disorders and Stroke study showed that rt-PA was an effective treatment for AIS, nowadays for use up to 4.5 h after onset. However, rt-PA still often fails in achieving rapid reperfusion, has relatively low recanalization rates and is associated with an increased
bleeding risk. Several attempts have been made to develop thrombolytics with a better risk-benefit profile than rt-PA, but no real impact on clinical practice was observed. In 1994, it was shown that
tenecteplase (rt-PA-TNK) had a higher
fibrin specificity than rt-PA, but its clinical use in AIS was described only in 2005. The recently reported results of a small phase 2B trial showed significantly better reperfusion and clinical outcome with rt-PA-TNK compared to rt-PA; patients were selected by CT perfusion and angiography, and treated within 6 h after
stroke onset. Currently, a phase 3 trial of rt-PA-TNK versus rt-PA is being planned in patients at an onset up to 4.5 h. The most
fibrin-specific recombinant
plasminogen activator desmoteplase originates from 1991, and its clinical development in AIS started in 2005.
Desmoteplase is in phase 3 development for the treatment of AIS between 3 and 9 h after onset in AIS patients presenting with occlusion or high-grade
stenosis.