Tissue plasminogen activators (recombinant tPA) convert plasminogen to plasmin. These drugs were shown to be effective in the treatment of stroke decades after the demonstration that they were effective for coronary artery occlusion. Alteplase and tenecteplase are the main genetically engineered forms of plasminogen activators. Tenecteplase has a higher fibrin specificity and longer duration of action compared to alteplase. In the following discussion, we use “tPA” to represent all tissue plasminogen activators.
The benchmark study organized by the National Institute of Neurological and Communicative Disorders and Stroke (see the NINCDS and Stroke rtPA Stroke Study Group in the references) provided evidence of benefit from intravenous tPA. Treatment within 3 h of the onset of symptoms led to a 30 percent increase in the number of patients who remained with little or no neurologic deficit when examined 3 months after the stroke; this benefit persisted when assessed 1 year later in the study by Kwiatkowski and associates. Two aspects are notable: the benefits extended to all types of ischemic strokes, including those caused by occlusion of small vessels (lacunes), and improvement was not apparent in the days immediately following treatment, only when patients were examined at 3 months.
We make a comment here about the historically important, seminal NIH study, in which tPA was administered in a dose of 0.9 mg/kg, 10 percent of which was given as an initial bolus, followed by an infusion of the remainder over 1 h. A dose of 90 mg was not exceeded, this being lower than the dose used for myocardial infarction. The relative improvement in neurologic state came at the expense of a 6 percent risk of symptomatic cerebral hemorrhage and 4 percent of insignificant hemorrhages seen on imaging, that is, a lower rate than in most previous studies but twice the expected rate without thrombolysis (some of the hemorrhages were into the area of infarction and did not cause symptomatic worsening). Patients were excluded from the study if they had massive infarctions (encompassing more than two-thirds of the territory of the middle cerebral artery), had high scores on a clinical stroke scale that was devised for the National Institutes of Health (NIH) study (available at: http://www.ninds .nih.gov/doctors/NIH_Stroke_Scale.pdf and from other sources) had uncontrolled hypertension, were more than 80 years of age, or had recently received anticoagulants (except aspirin). Further analysis of the NINCDS trial revealed that patients who were treated earliest within the 3-h time frame had more benefit than those treated later; indeed, the administration of tPA in the time between 2.5 and 3 h after the stroke was of less value. One trial has suggested that a lower dose of tPA (0.6 mg/kg) is non-inferior to the standard dose in a population of predominantly Asian patients (Anderson et al 2016).
For tenecteplase, doses of 0.25 mg/kg or 0.4 mg/kg have been used for thrombolysis and achieved comparable results. The trial reported by Logallo comparing tenecteplase at the higher dose to alteplase showed no difference between groups in clinical outcomes but other trials, such as the one by Parsons et al and by Campbell et al showed an improved rate of revascularization before thrombectomy, in the latter of 22% compared to 10% with alteplase using a lower dose of 0.25 mg/kg.