- Researchers investigated if intra-arterial alteplase improves functional outcomes after successful mechanical thrombectomy in patients with large vessel occlusion strokes.
- This randomized trial at 14 centers assigned 440 patients to receive either adjunctive intra-arterial alteplase or thrombectomy alone.
- Excellent functional outcomes occurred in 57.5 percent of alteplase patients versus 42.5 percent of controls (risk difference 15.0 percent, P=.002).
- The researchers concluded that adjunctive intra-arterial alteplase significantly improves 90-day functional recovery without increasing symptomatic intracranial hemorrhage risk.
- Clinicians should note the higher mortality rate of 12.1 percent in the alteplase group, which requires further investigation.
Optimizing Reperfusion Beyond the Large Vessel Occlusion
Endovascular thrombectomy has become the standard of care for achieving rapid recanalization in patients with large vessel occlusions [1, 2, 3]. However, many patients fail to regain functional independence despite successful macrovascular opening, a phenomenon often attributed to microcirculatory failure (the persistent lack of perfusion in the smallest distal vessels) [4, 5]. While systemic intravenous thrombolysis is frequently used before or during intervention, its efficacy in resolving distal emboli that persist after mechanical clot removal remains a subject of clinical debate [6]. To address this residual perfusion deficit, researchers recently investigated whether delivering thrombolytics directly into the affected arterial bed improves functional recovery. The findings suggest that adjunctive intra-arterial thrombolysis significantly increases the likelihood of an excellent functional outcome, though clinicians must carefully weigh this benefit against an unexpected rise in mortality.
Trial Design and Patient Selection
The researchers conducted a randomized, open-label trial with blinded outcome assessment across 14 stroke centers in Spain between December 11, 2023, and November 26, 2025. The trial (NCT05797792) focused on patients presenting with acute ischemic stroke due to large vessel occlusion who underwent mechanical thrombectomy within 24 hours of symptom onset. To isolate the effects of adjunctive thrombolysis on microvascular flow, the investigators specifically selected patients who had already achieved successful macrovascular reperfusion. This was defined as an expanded Treatment in Cerebral Ischemia score of 2b50 to 3, a grading system indicating that the primary occlusion has been cleared and at least half of the downstream territory is being perfused, even if complete capillary-level reperfusion is lacking. The screening process required a high volume of cases to identify this specific clinical subset. Of the 3786 patients treated with thrombectomy during the study period, 2776 (73%) fulfilled the initial angiographic criteria for successful recanalization. From this group, 440 patients met all inclusion criteria and underwent randomization. Ultimately, 433 patients were treated as randomized, comprising a cohort with a median age of 76 years (interquartile range, 75 to 78 years). The study population was 51% female, providing a representative sample of the demographic most frequently affected by large vessel occlusion strokes.
Targeted Microvascular Thrombolysis Protocol
The clinical protocol for the intervention group involved the administration of intra-arterial alteplase at a dose of 0.225 mg/kg, with a total maximum dose capped at 20 mg/kg. This pharmacological adjunct was delivered via a catheter-directed infusion over a period of 15 minutes immediately following the mechanical procedure. A total of 221 patients were assigned to this combined treatment arm. By delivering the thrombolytic agent directly into the affected arterial territory, the researchers aimed to dissolve distal microvascular obstructions that often persist even after the primary large vessel occlusion has been successfully cleared. In contrast, the control group consisted of 219 patients who received thrombectomy alone, the current standard surgical intervention for large vessel occlusion. This control group did not receive any adjunctive intra-arterial thrombolytic therapy after achieving successful recanalization. Comparing these two cohorts allowed the investigators to isolate the specific impact of late-stage microvascular thrombolysis on long-term functional recovery and residual tissue perfusion. By maintaining a strict 15-minute infusion window for the alteplase, the protocol sought to balance the potential for improved capillary flow against the known risks of hemorrhagic transformation associated with systemic or high-dose thrombolytic agents.
Functional Recovery and Perfusion Gains
The primary outcome of the trial focused on the achievement of an excellent functional outcome at 90 days, defined as a score of 0 or 1 on the modified Rankin Scale (a standard clinical tool measuring the degree of disability or dependence in daily activities). Among the patients who received the adjunctive treatment, 57.5% (123/214) reached this level of functional independence, compared to 42.5% (93/219) in the group treated with thrombectomy alone. This represents an adjusted risk difference of 15.0% (95% CI, 5.7% to 24.3%; P = .002). For practicing neurologists and emergency physicians, this absolute increase of 15 percent suggests that adding intra-arterial alteplase significantly boosts the probability of a patient returning to a state of no significant disability following a large vessel occlusion. Beyond the primary endpoint, the study evaluated six secondary outcomes to determine the physiological impact of the thrombolytic adjunct on follow-up computed tomography perfusion scans. The researchers found that residual hypoperfusion (a state of persistent low blood flow in brain tissue despite the successful reopening of the primary blocked artery) occurred in 28.6% (55/192) of the alteplase group versus 50.5% (96/190) of the thrombectomy alone group. This resulted in an adjusted risk difference for residual hypoperfusion of -22.0% (95% CI, -31.5% to -12.4%; P < .001), indicating that the pharmacological intervention effectively addressed microvascular obstructions that mechanical thrombectomy could not reach. Despite these gains in perfusion and the primary functional measure, four of the six secondary outcomes showed no significant between-group differences, highlighting that the benefits of the intervention were most pronounced in specific measures of tissue blood flow and overall disability scores.
Safety Signals and Mortality Concerns
The primary safety concern with any thrombolytic agent is the risk of symptomatic intracranial hemorrhage (bleeding in the brain that causes a measurable worsening of the patient's neurological status). In this trial, symptomatic intracranial hemorrhage occurred in 1.4% (3/214) of the alteplase group compared to 0.5% (1/219) of the control group. While the incidence was numerically higher in patients receiving the adjunctive infusion, the difference did not reach statistical significance. The adjusted odds ratio for symptomatic intracranial hemorrhage was 3.10 (95% CI, 0.32 to 30.0; P = .33), suggesting that the risk of major bleeding complications was not significantly elevated by the addition of low-dose intra-arterial alteplase. Despite the lack of a significant increase in bleeding events, the researchers observed a concerning trend regarding patient survival. Mortality at 90 days was 12.1% (26/214) in the alteplase group versus 6.4% (14/219) in the thrombectomy alone group. This finding represents an adjusted risk difference for mortality of 5.9% (95% CI, 0.5% to 11.3%; P = .03). This statistically significant increase in deaths stands in stark contrast to the improved functional outcomes reported in the primary analysis. For clinical practice, this creates a complex shared decision-making scenario: physicians must weigh a 15 percent absolute increase in functional independence against a nearly 6 percent increase in mortality when considering the use of adjunctive thrombolysis. The authors noted that the reasons for this higher mortality rate remain unclear and warrant further investigation before this protocol can be universally adopted.
References
1. Berkhemer OA, Fransen P, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. New England Journal of Medicine. 2014. doi:10.1056/nejmoa1411587
2. Saver JL, Goyal M, Bonafé A, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. New England Journal of Medicine. 2015. doi:10.1056/nejmoa1415061
3. Bush C, Kurimella D, Cross LJS, et al. Endovascular Treatment with Stent-Retriever Devices for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. PLoS ONE. 2016. doi:10.1371/journal.pone.0147287
4. Abbas A, Elfil M, Sabet H, et al. ABSTRACT NUMBER: ESOC2026A2290 INTRA-ARTERIAL THROMBOLYTICS AFTER ENDOVASCULAR THROMBECTOMY FOR ACUTE ISCHEMIC STROKE: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. European Stroke Journal. 2026. doi:10.1093/esj/aakag023.1053
5. Chen Y, Bao M, Deng Z, et al. ABSTRACT NUMBER: ESOC2026A1189 ADJUNCTIVE INTRA-ARTERIAL ALTEPLASE AFTER NEAR-COMPLETE OR COMPLETE REPERFUSION IN ACUTE ISCHEMIC STROKE: A POST HOC ANALYSIS OF THE PEARL TRIAL. European Stroke Journal. 2026. doi:10.1093/esj/aakag023.588
6. LeCouffe NE, Kappelhof M, Treurniet KM, et al. A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke. New England Journal of Medicine. 2021. doi:10.1056/nejmoa2107727