INTRODUCTION: The standard therapy for acute low- and intermediate-risk pulmonary embolism (PE) is anticoagulation, while concomitant systemic thrombolysis is reserved only for high-risk patients. Studies reporting thrombolysis in the former categories have yielded mixed results.

METHODS: Two databases and two trial registers were searched for randomized- and non-randomized trials. The Mantel-Haenszel method, along with a fixed-effect model, was used for analysing dichotomous outcomes.

RESULTS: Sixteen trials were included. Concomitant use of tPA analogues resulted in lower all-cause mortality (OR = 0.53;95%-CI:0.32-0.89;p = 0.02), PE recurrence (OR = 0.47;95%-CI:0.24-0.90; p = 0.01) and, treatment-escalations (OR = 0.39;95%-CI:0.25-0.61;p < 0.00001) while causing a higher incidence of major- (OR = 2.84;95%-CI:1.82-4.43; p < 0.00001) and minor-bleeding (OR = 4.31;95%-CI:3.26-5.71;p < 0.00001). Subgroup analysis based on the type of tPA used showed similar results except for the significantly lower major-bleeding with alteplase compared to tenecteplase (p = 0.003) and a lower incidence of bleeding events with low dosage while maintaining relatively similar treatment efficacy.

CONCLUSIONS: Systemic thrombolysis significantly reduced all-cause mortality, PE recurrence, and treatment escalations but increased major and minor bleeding risk, with low-dose alteplase causing fewer bleeding complications compared to full-dose therapy/tenecteplase. Although the included trials showcased substantial sample-sizes and standardized dosing protocols, their baseline imbalances introduced potential confounding bias. Notably, mortality reduction lost statistical-significance upon excluding non-randomized trials and trials with baseline imbalances.

REGISTRATION: This paper was registered on PROSPERO (CRD42024553660).