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Life sciences · Review
International Journal of Angiology · September 21, 2026
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Abstract Intermediate–high-risk pulmonary embolism (IHR-PE) remains a difficult condition to manage. These patients are hemodynamically stable but have both right ventricular (RV) dysfunction and elevated troponin levels, corresponding to American Heart Association/American College of Cardiology (AHA/ACC) 2026 Category C. Anticoagulation alone may not reduce RV afterload quickly enough, whereas full-dose systemic thrombolysis is associated with a substantial risk of bleeding, including intracranial hemorrhage (ICH) rates of around 2.0%. Low-dose alteplase (≤ 50 mg) has been proposed as an alternative approach. However, the available evidence on its safety and efficacy at this dose has not yet been comprehensively synthesized. This systematic review and meta-analysis was prospectively registered in PROSPERO (CRD420261389578) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched PubMed/MEDLINE, Europe PMC, and Cochrane CENTRAL through May 9, 2026, without restricting publication date. Eligible studies included randomized controlled trials (RCTs) and controlled observational studies involving adults with IHR-PE, defined by the European Society of Cardiology 2019 criteria or an equivalent classification, including AHA/ACC 2026 Category C. Patients received systemic intravenous alteplase at a dose of ≤ 50 mg or anticoagulation alone. Two reviewers independently completed study screening, data extraction, and risk-of-bias assessment using Risk of Bias Tool 2 and the Newcastle–Ottawa Scale. The coprimary outcomes were hemodynamic decompensation within 30 days and major bleeding according to the International Society on Thrombosis and Haemostasis definition. Pooled risk ratios (RRs) were calculated using a random-effects model with the DerSimonian–Laird method. We also performed five prespecified sensitivity analyses and two prespecified subgroup analyses. Ten studies met the inclusion criteria, including three RCTs and seven controlled observational studies. Together, they enrolled 978 patients from five countries, with 476 receiving low-dose alteplase and 502 receiving anticoagulation alone. Low-dose alteplase significantly reduced the risk of hemodynamic decompensation (RR: 0.16, 95% confidence interval [CI]: 0.06–0.46; p = 0.0007; I 2 = 0%; five studies), with event rates of 1.5 versus 13.0%. Major bleeding was numerically more frequent in the alteplase group (4.8 vs. 2.5%), but the difference was not statistically significant (RR: 1.85, 95% CI: 0.65–5.27; p = 0.25; I 2 = 0%; five studies). Five additional studies, including 464 patients, reported no major bleeding events in either treatment arm. Short-term all-cause mortality was significantly lower with alteplase (RR: 0.41, 95% CI: 0.19–0.84; p = 0.02; I 2 = 0%; six studies), although the only multicenter RCT, STRATIFY, reported four deaths in the alteplase group and none in the heparin group at the 3-month follow-up. Minor bleeding occurred more often with alteplase (RR: 2.03, 95% CI: 1.33–3.09; p = 0.001; I 2 = 0%; seven studies). Recurrent pulmonary embolism was less frequent in the alteplase group, but the difference did not reach statistical significance (RR: 0.38, 95% CI: 0.12–1.26; p = 0.11; I 2 = 0%; five studies; 1.3 vs. 5.2%). Across seven studies, ICH occurred in 1 of 378 patients (0.26%) treated with alteplase. The primary efficacy findings remained stable in all prespecified sensitivity analyses and were consistent across subgroups defined by study design, risk-stratification criteria, alteplase dose, and infusion duration. No significant subgroup-by-treatment interactions were identified (all p > 0.23). Begg's test did not indicate publication bias for any outcome (p ≥ 0.14), and trim-and-fill analysis identified one potentially missing study each for hemodynamic decompensation and major bleeding; adjusted pooled estimates were materially unchanged. Low-dose alteplase (≤ 50 mg) was associated with significant reductions in hemodynamic decompensation and short-term mortality among patients with IHR-PE, without a significant increase in major bleeding. The observed rate of ICH was substantially lower than that reported with full-dose thrombolysis. However, confidence in the mortality findings is limited by the conflicting 3-month results from the only multicenter RCT and the predominance of observational studies in the available evidence. These findings help address the dose-specific evidence gap recognized in the 2026 AHA/ACC guideline for Category C patients and highlight the need for adequately powered randomized trials, particularly PEITHO-3.