Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Background: Intravenous thrombolysis using tissue plasminogen activator (tPA) improves significantly the neurologic function in patients with acute ischemic stroke (AIS). However, it brings financial burden to patients and is associated with symptomatic intracranial hemorrhage (SICH). Whether low-dose tPA can effectively reduce SICH and has the same efficacy as standard-dose tPA is still controversial. Methods: We searched for English clinical trials published before March, 2017on the comparison of the efficacy and safety between low and standard dose of tPA in the treatment of AIS using MEDLINE, Embase, and Cochrane Library. The modified Rankin scale (mRS) score was used as the primary efficacy outcome. The mRS1 corresponded to 0-1, whereas mRS2 corresponded to 0-2. The SICH and mortality were adopted as primary safety outcomes. Results: Twelve high-quality studies were selected, including 7686 patients (low-dose: 2888, standard-dose: 4798). With no statistical heterogeneity, the fixed effects model was adopted in the analysis. Similarly to standard doses, low-dose tPA improved the mRS scores (mRS1: odds ratio [OR] = .92, 95% confidence interval [CI].84-1.02; P = .12; mRS2: OR = .97, 95% CI.88-1.08; P = .57). Compared with standard-dose tPA, low-dose tPA reduced the incidence of SICH (by National Institute of Neurological Disorders and Stroke [NINDS] definition: OR = .71, 95% CI.57-0.89; P = .003; by Safe Implementation of Thrombolysis in Stroke Monitoring Study [SITS-MOST] definition: OR = .64, 95% CI.42-0.99; P = .04), while both reduced mortality (OR = .87, 95% CI.74-1.02; P = .08). Conclusions: Low-dose tPA is comparable to standard-dose tPA in improving the neurologic function and reducing mortality in AIS patients. Moreover, low-dose tPA can reduce the incidence of SICH compared with standard-dose tPA. Therefore, low-dose tPA is highly recommended in AIS patients.