Low-dose intravenous tissue plasminogen activator for acute ischaemic stroke: an alternative or a new standard?

Abstract

BackgroundWith the recent publication of a large clinical trial on the use of a lower dose of intravenous (IV) tissue plasminogen activator (tPA) for acute ischaemic stroke (AIS), the concept of using a different dose has been debated. We intend to review the literature on using a lower dose of IV tPA and gain a better understanding of the impact of different IV doses on the treatment of patients with AIS.MethodsA comprehensive literature search of the related topics in PubMed, EMBASE, Web of Science and MEDLINE was carried out. Key words used include low dose IV tPA, thrombolysis, Alteplace and tPA for AIS. Findings were tabulated according to the size of the cohort studied, outcome, adverse event and level of evidence. The results of all studies using lower doses were analysed for efficacy and adverse events.ResultsFrom 1992 to 2016, there were 23 trials that included 10 950 patients published on the use of lower doses of IV tPA for AIS. Doses ranged from 0.5, 0.6, 0.75 to 0.85 mg/kg. Most were observational, retrospective and registry studies. One was a prospective open-label randomised controlled trial. 13 trials combined lower doses of IV tPA with a glycoprotein IIb/IIIa inhibitor or thrombectomy. Patients treated with lower doses of IV tPA showed a trend of lower rate of symptomatic intracranial haemorrhage and mortality at 3 months but slightly more disability.ConclusionsLower doses of IV tPA showed less haemorrhagic events but were not more effective compared with the standard dose. The optimal low dose of IV tPA remains unclear. Patients with AIS with a high risk of developing sypmtomatic intracranial haemorrhage might benefit from lower dose IV tPA, such as 0.6 mg/kg.

The safety and effectiveness of early anti-platelet therapy after alteplase for acute ischemic stroke: A meta-analysis

“…The difference was that the dose of alteplase was adjusted in one study [18], which was 0.6 mg/kg. Previous studies [22][23][24][25][26] showd that compared with the 0.9 mg/kg dose group, there was no difference in the main efficacy indicators and safety indicators in the low-dose alteplase group. A study showed that starting anti-platelet-aggregation therapy as early as the beginning of intravenous thrombolysis, or as late as 120 min after thrombolytic therapy, which was much earlier than the 24 h recommended by current guidelines, benefited the patients of AIS, but this conclusion needs to be further confirmed by more high-quality studies.…”

Acute Reperfusion Therapies for Acute Ischemic Stroke

“…These pivotal trials also became the basis for eligibility of patients to receive the thrombolytic therapy along with the mode and dose of medication administration. The alteplase dose is calculated according to the patient's body weight (0.9 mg/kg), with a maximum dose of 90 mg, of which 10% is given as a loading bolus over 1 min and the remainder administered through an intravenous infusion over 1 h. Notably, there are some regions including Japan where a smaller dose of 0.6 mg/kg is utilized owing to concerns for increased complications and bleeding risks in their specific patient populations [18,19]. These regional recommendations have been supported by the results of the ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study) that enrolled 3310 predominantly Asian patients to receive either the standard 0.9 mg/kg or a lower 0.6 mg/kg of IV alteplase within 4.5 h of stroke onset [20].…”

Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke

“…However, other relevant clinical trials have used different tPA doses. For instance, the ECASS trial 7 used a higher infusion dose of 1.1 mg/kg, while doses as low as 0.3 mg/kg have also been tested 8 . The J-MARS study 9 evaluated the use of 0.6 mg/kg intravenous dose for the treatment of ischaemic stroke and found low levels of ICH (<5%) and relatively high levels of functional outcome at 3 months (>30%).…”