Highlight
– Individual participant data (IPD) meta-analysis of 6 randomized trials (n=2313) comparing IV alteplase plus endovascular treatment (EVT) versus EVT alone for anterior circulation large-vessel occlusion stroke.
– IV alteplase was associated with a modestly higher risk of any intracranial hemorrhage (ICH) and of parenchymal hematoma (PH1/PH2) (adjusted ORs 1.23 and 1.54, respectively).
– Both asymptomatic and symptomatic ICH were linked to worse functional outcomes; however, IVT may still confer net benefit through improved rates of early/final reperfusion.
Background
Acute ischemic stroke caused by anterior circulation large-vessel occlusion (LVO) carries high morbidity and mortality. Current acute care pathways in EVT-capable centers often confront the decision whether to give intravenous thrombolysis (IVT; usually alteplase) before mechanical thrombectomy (bridging therapy) when patients present within the eligible time window and meet criteria for IVT.
The potential benefit of IVT before EVT includes earlier partial or complete fibrinolysis, clot softening that may facilitate retrieval, and increased rates of early reperfusion. Conversely, thrombolysis may increase the risk of hemorrhagic transformation, particularly parenchymal hematoma, which is associated with worse outcomes. Randomized trials in recent years have directly compared EVT alone with IVT plus EVT, but questions persist about the frequency, subtypes, and outcome associations of ICH in these strategies.
Study design
The cited individual participant data (IPD) meta-analysis (Zhou et al., JAMA Neurology 2025) pooled patient-level data from randomized clinical trials comparing EVT alone versus IV alteplase plus EVT for anterior circulation LVO presenting directly to EVT-capable centers. The systematic search encompassed PubMed/MEDLINE through March 9, 2023; six trials contributed data, totaling 2313 participants (1160 assigned to IVT+EVT and 1153 to EVT alone).
Key methodological features:
- Outcomes were categorized using the Heidelberg Bleeding Classification into hemorrhagic infarction types (HI1, HI2), parenchymal hematoma types (PH1, PH2), and other ICH categories, and were classified as symptomatic or asymptomatic ICH.
- Analyses used mixed models with multinomial or binary regression on pooled IPD and adjusted for relevant covariates; a random-effects model accounted for between-trial heterogeneity.
- Primary analysis focused on rates of any ICH, ICH subtypes, and the association between ICH (and subtypes) and 90-day functional outcomes measured by the modified Rankin Scale (mRS).
Key findings
Population and overall rates
The pooled cohort included 2313 participants (median age 71 years, 44% female). Any ICH occurred in 768 of 2261 participants with available hemorrhage data (34%).
Effect of IV alteplase on ICH
– Any ICH: IVT plus EVT was associated with a modestly increased risk of any ICH (411 of 1133 [36%] vs 357 of 1128 [32%]; adjusted odds ratio [OR], 1.23; 95% CI, 1.02–1.49; P = .03).
– Any parenchymal hematoma (PH1 or PH2): IVT increased the risk of parenchymal hematoma (82 of 1133 [7%] vs 61 of 1128 [5%]; adjusted OR, 1.54; 95% CI, 1.02–2.34; P = .04).
– Subtypes: The authors evaluated Heidelberg-defined subtypes (HI1, HI2, PH1, PH2, other) and found a graded relationship with outcome (see below), with IVT contributing disproportionately to parenchymal hematomas compared with EVT alone.
ICH and functional outcomes
– Compared with participants without ICH, both asymptomatic and symptomatic ICH were associated with worse 90-day functional outcomes.
– Asymptomatic ICH: adjusted common OR for worse mRS, 0.55 (95% CI, 0.46–0.65) — indicating poorer outcomes compared with no ICH.
– Symptomatic ICH: adjusted common OR for worse mRS, 0.08 (95% CI, 0.05–0.13) — a strong association with poor outcome.
– Radiologic pattern correlated with outcome in a graded fashion: hemorrhagic infarction patterns were less detrimental than parenchymal hematomas, and PH2 carried the worst prognosis.
Net clinical interpretation
Although IV alteplase increased ICH—especially parenchymal hematoma—the authors emphasize that the net clinical effect of IVT is complex. IVT may increase rates of early reperfusion and final successful reperfusion, which are strongly associated with improved functional outcomes. Thus, the modest increase in hemorrhagic complications could be offset by reperfusion benefits in some patients.
Expert commentary
Clinical implications
This IPD meta-analysis provides high-resolution data on bleeding risks after contemporary EVT with or without preceding IV alteplase. The takeaways for clinicians in EVT-capable centers are nuanced:
- IVT modestly increases the absolute risk of ICH (≈4 percentage points for any ICH in this pooled cohort) and increases the relative risk of parenchymal hematoma by roughly 50% (adjusted OR 1.54). Parenchymal hematoma—particularly PH2—remains the most clinically consequential subtype.
- Any decision on bridging therapy should weigh the higher hemorrhage risk against potential benefits: earlier reperfusion, possible increases in final successful reperfusion, and outcomes that can be improved by timely vessel recanalization.
- Individualization is key. Patient-level factors that influence bleeding risk (age, comorbidity, baseline infarct size/aspect score, anticoagulant use, and blood pressure) should be considered when deciding on IVT before EVT. The trials and IPD meta-analysis were limited to patients presenting directly to EVT-capable centers with anterior circulation LVO, so applicability to transfer scenarios or posterior circulation strokes may differ.
Mechanistic considerations
Thrombolysis increases the risk of hemorrhagic transformation by promoting fibrinolysis in ischemic tissue, which can worsen blood–brain barrier disruption. In the setting of large infarct cores, reperfusion on a fragile microvascular bed may precipitate parenchymal hematoma. Conversely, partial clot lysis or microfragmentation induced by IVT prior to thrombectomy can facilitate retrieval and increase the likelihood of timely reperfusion.
Guideline and policy context
Major stroke guidelines have traditionally recommended IV alteplase for eligible patients presenting within 4.5 hours even when EVT is planned, based on historic trial data showing benefit of IVT and the added value of combined therapy in many settings. The recent randomized trials comparing direct EVT to bridging therapy have prompted reappraisal; this IPD meta-analysis adds clarity on bleeding risk, but it does not by itself settle the overall benefit–harm calculus for all patients. Local systems, trial evidence, and patient-specific factors should guide practice.
Limitations and interpretive cautions
– Heterogeneity: Although this IPD analysis used random-effects models and trial-level adjustments, differences in imaging protocols, definitions of symptomatic ICH, IVT dosing, procedural techniques, and peri-procedural care across trials remain potential sources of heterogeneity.
– Generalizability: The analysis focused on patients presenting directly to EVT-capable centers with anterior circulation LVO and may not apply to patients transferred from non-capable centers (drip-and-ship), to posterior circulation strokes, or to patients outside typical IVT time windows.
– Residual confounding: Even with adjustment, unmeasured confounders could influence observed associations, and subgroup effects (for example, by ASPECTS, occlusion location, or pre-stroke disability) may be underpowered in pooled analyses.
Clinical takeaways
– Expect a modest increase in any ICH and a statistically significant increase in parenchymal hematoma when IV alteplase is administered before EVT in patients with anterior circulation LVO presenting directly to EVT centers.
– Recognize that both symptomatic and asymptomatic ICH are associated with worse 90-day outcomes; parenchymal hematomas confer the greatest risk.
– Decisions about bridging therapy should be individualized, incorporating patient factors, local workflow (e.g., expected door-to-puncture time), and multidisciplinary judgment. The modest bleeding risk does not automatically preclude IVT in eligible patients but should be part of shared decision-making and informed consent where possible.
Research and practice gaps
- Identification of subgroups most likely to benefit or be harmed by bridging therapy (for example, large infarct cores, extensive leukoaraiosis, or patients on anticoagulants) requires further pooled analyses and prospective trials.
- Standardization of imaging protocols and bleeding definitions across future trials would improve comparability and help refine risk prediction tools for ICH after reperfusion therapies.
- Operational questions remain: does IVT meaningfully affect first-pass effect, device selection, or procedural complications in ways that modify outcomes beyond hemorrhage rates?
Conclusion
This IPD meta-analysis shows that adding IV alteplase to EVT modestly increases intracranial hemorrhage—particularly parenchymal hematoma—yet the clinical impact must be weighed against benefits in reperfusion. Both asymptomatic and symptomatic ICH correlate with worse outcomes, underscoring the clinical relevance of bleeding events. For now, clinicians should individualize the choice of bridging therapy, balancing hemorrhagic risk against potential reperfusion advantages until further data clarify subgroup-specific net benefit.
Funding and clinicaltrials.gov
Funding sources and trial registrations are reported in the underlying randomized trials and in the IPD meta-analysis (Zhou et al., JAMA Neurol 2025). Readers should consult the primary JAMA Neurology article and the original trial publications for specific funding disclosures and ClinicalTrials.gov identifiers for each trial.
References
1. Zhou Y, Zhang L, Cavalcante F, et al; IRIS collaborators. Intracranial Hemorrhage in Patients With Stroke After Endovascular Treatment With or Without IV Alteplase: An Individual Participant Data Meta-Analysis. JAMA Neurol. 2025 Oct 1;82(10):1031-1039. doi:10.1001/jamaneurol.2025.2610.
2. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46–e110.
