1. Publication
- Title: Intra-Arterial Alteplase After Successful Endovascular Reperfusion in Acute Stroke: The PEARL Randomized Clinical Trial
- Acronym: PEARL
- Year & Journal: JAMA, published October 13, 2025 (2025;334(19):1728-1739)
- Citation: Writing Committee for the PEARL Investigators. Intra-Arterial Alteplase After Successful Endovascular Reperfusion in Acute Stroke: The PEARL Randomized Clinical Trial. JAMA. 2025;334(19):1728-1739. doi:10.1001/jama.2025.16876
2. Context & Rationale
Background: Despite successful macrorecanalization (eTICI ≥2b50) after thrombectomy, up to half of large-vessel-occlusion stroke patients remain dependent or dead at 90 days — a discordance attributed partly to microcirculatory impairment causing ineffective tissue-level reperfusion despite vessel patency. Prior trials of adjunctive intra-arterial thrombolysis after successful EVT gave mixed results (CHOICE positive, POST-TNK and POST-UK negative).
Research Question/Hypothesis: In patients with anterior-circulation LVO stroke who achieve successful reperfusion after thrombectomy, does adjunctive intra-arterial alteplase improve 90-day functional outcome (mRS 0-1) compared with standard treatment?
Why This Matters: Adds a fourth major RCT to a field with conflicting prior results, testing whether targeting residual microcirculatory impairment via IA thrombolysis can close the gap between vessel patency and clinical recovery.
3. Design & Methods
- Study Type: Multicenter, randomized, open-label, assessor-blinded-endpoint clinical trial
- Setting & Centers: 28 hospitals, China; enrolled August 1, 2023 – October 16, 2024, final follow-up January 7, 2025
- Population:
- Inclusion: Anterior-circulation LVO stroke within 24h of onset, successful reperfusion (eTICI ≥2b50) after thrombectomy; guideline-based IV thrombolysis allowed
- Exclusions: Not detailed in available trial text
- Intervention: Intra-arterial alteplase, 0.225 mg/kg (max 20mg) (n=164)
- Comparator: Standard treatment (n=160)
- Randomization: 1:1, block size 4, stratified by center and IV thrombolysis status; 324 patients randomized (median age 68y, 30.6% female)
- Blinding: Open-label treatment, assessor-blinded outcome evaluation
- Statistical Power & Follow-Up: Primary outcome: mRS 0-1 at 90 days. Safety: symptomatic ICH within 36h, 90-day mortality, any ICH within 36h.
4. Key Results
324 patients randomized; 1 per group lost to follow-up.
Outcome | IA Alteplase | Standard Treatment | Effect Size | 95% CI | p-value | Notes |
mRS 0-1 at 90 days (primary) | 73/163 (44.8%) | 48/159 (30.2%) | Adjusted RR 1.45 | 1.08–1.96 | — | Significant benefit |
Functional independence (mRS 0-2, secondary) | 53.0% | 29.3% | Common OR 2.6 | 1.7–3.8 | <0.001 | Large effect |
90-day mortality | 10.4% | 19.0% | Not reported as RR | — | 0.04 | Significantly reduced with IA alteplase |
Symptomatic ICH | 3.6% | 2.7% | Not reported | — | 0.75 | No significant safety difference |
5. Internal Validity Assessment
- Randomization & Allocation: Web-based central randomization, block size 4, stratified by center and IV thrombolysis status, sequences generated by independent statisticians uninvolved in enrollment — strong concealment.
- Protocol Adherence & Separation: All participants underwent thrombectomy and standard guideline-based management; IA alteplase dosing standardized.
- Blinding & Detection Bias: Open-label treatment (unavoidable for an intra-arterial procedure) but assessor-blinded outcome evaluation — reduces detection bias for the functional-outcome primary endpoint.
- Missing Data & Sensitivity Analyses: Minimal loss to follow-up (1 patient per group of 324).
- Overall Internal Validity Conclusion: Strong — rigorous randomization, assessor-blinded outcomes, minimal attrition, and a large, statistically robust effect size (common OR 2.6) with a concurrent mortality benefit and no safety penalty support high confidence in this positive result.
6. External Validity Assessment
- Population Representativeness: Chinese, 28-center, anterior-circulation LVO population achieving successful thrombectomy reperfusion — directly representative of the population for whom this adjunctive strategy would be considered.
- Practice Context: Requires thrombectomy capability plus additional IA alteplase administration expertise/protocol — an incremental procedural step for centers already performing EVT.
- Overall External Validity Conclusion: Good for EVT-capable stroke centers; single-country (China) design and mixed prior-trial results (CHOICE positive, POST-TNK/POST-UK negative) suggest some caution before assuming universal generalizability.
7. Strengths & Limitations
Strengths:
- Large effect size with concurrent primary-outcome and mortality benefit, and no safety penalty (similar sICH rates)
- Assessor-blinded outcome evaluation strengthens an open-label procedural trial
- Minimal loss to follow-up
- Adds important positive data to a field with conflicting prior trial results
Limitations:
- Open-label treatment delivery
- Single-country (China) trial
- Contrasts with negative results from POST-TNK and POST-UK (different thrombolytic agents/doses) — field-level heterogeneity in this research question remains unresolved
- Relatively modest total sample size (324) for a field with such conflicting prior signals
8. Interpretation & Practice Impact
- Clinical Implications: Supports considering adjunctive IA alteplase after successful thrombectomy reperfusion in similar populations, given the large, statistically robust functional and mortality benefit without excess bleeding risk.
- Mechanistic Coherence: Consistent with the microcirculatory-impairment hypothesis — clearing residual microvascular thrombus/dysfunction after macrovascular recanalization plausibly explains the observed benefit.
- Systems-Level Takeaway: Per a 2025 pooled meta-analysis (ATLAS-ER) of 6 RCTs, both ANGEL-TNK and PEARL (2025) showed benefit while earlier trials (POST-TNK, POST-UK) did not — suggesting the field is converging toward a positive signal, though agent-specific and dose-specific factors remain to be fully clarified.
9. Controversies & Subsequent Evidence
- Editorial Commentary: An accompanying JAMA commentary ("Intra-Arterial Thrombolytics During Thrombectomy for Ischemic Stroke — End of the Story or a New Beginning?") engages directly with the field's conflicting evidence base.
- Guideline Integration: A 2025 meta-analysis (Doheim et al., Ann Neurol) and a separate systematic review (ATLAS-ER) of 6 RCTs found IA thrombolysis improved excellent functional outcomes overall, with benefit appearing greater in trials including TICI 2b-3 (vs 2c-3) patients — PEARL and ANGEL-TNK (both 2025, both positive) now anchor the positive side of this evidence base, while POST-TNK and POST-UK anchor the negative side.
10. Summary & Executive Takeaway
Summary: PEARL randomized 324 Chinese patients with anterior-circulation LVO stroke and successful thrombectomy reperfusion to adjunctive IA alteplase or standard treatment. mRS 0-1 at 90 days was significantly higher with IA alteplase (44.8% vs 30.2%, adjusted RR 1.45; common OR 2.6 for the full mRS shift, P<0.001), with reduced mortality (10.4% vs 19.0%, P=0.04) and no excess symptomatic ICH.
Overall Takeaway: PEARL adds a large, positive, methodologically rigorous trial to a genuinely mixed evidence base on adjunctive IA thrombolysis after successful EVT — alongside the concurrently positive ANGEL-TNK trial, 2025 represents a turning point toward favorable evidence for this strategy, though the negative POST-TNK/POST-UK trials mean this is not yet a settled question.
11. Bibliography
- Renu A, Millán M, San Román L, et al. Effect of intra-arterial alteplase vs placebo following successful thrombectomy on functional outcomes (CHOICE). JAMA. 2022;327:826-835.
- Huang J, Yang J, Liu C, et al. Intra-Arterial Tenecteplase Following Endovascular Reperfusion (POST-TNK). JAMA. 2025;doi:10.1001/jama.2024.23466
- Doheim MF, Mohammaden MH, Jumah A, et al. Adjunctive thrombolytics after successful endovascular reperfusion: systematic review and meta-analysis (ATLAS-ER). Ann Neurol. 2025.