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PEARL

Intra-arterial alteplase for acute ischaemic stroke after mechanical thrombectomy (PEARL): rationale and design of a multicentre, prospective, open-label, blinded-endpoint, randomised controlled trial

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Year of Publication: 2025

Authors: Xinguang Yang, Xiongjun He, Dong Pan, ..., Yamei Tang

Journal: BMJ Open

Citation: BMJ Open 2024:14:e091059. doi:10.1136/bmjopen-2024-091059

Link: https://doi.org/10.1136/bmjopen-2024-091059

PDF: https://www.researchgate.net/publication...mxpY2F0aW9uIn19

Clinical Question

Is intra-arterial alteplase after mechanical thrombectomy effective and safe for improving neurological outcomes in patients with acute ischemic stroke and large-vessel occlusion?

Bottom Line

The PEARL study is designed to test the superiority of intra-arterial alteplase after mechanical thrombectomy over standard medical treatment alone for acute ischemic stroke, hypothesizing that it will improve neurological recovery without significantly increasing the risk of symptomatic intracranial hemorrhage or mortality.

Major Points

  • The PEARL study is a multicenter, prospective, open-label, blinded-endpoint, randomized controlled trial in China.
  • The trial will compare intra-arterial alteplase plus standard medical treatment to standard medical treatment alone after mechanical thrombectomy.
  • The primary outcome is the proportion of patients with a 90-day modified Rankin Scale (mRS) score of 0-1, indicating an excellent outcome.
  • The study aims to enroll 324 participants, with 162 in each group, to test for superiority.
  • The study's primary strength is its rigorous randomized design, which is intended to provide high-level evidence for a Chinese population, filling a gap in existing research.
  • A key limitation is that the findings may have limited generalizability to other ethnic groups due to the study population being predominantly Han Chinese.
  • The open-label design is a limitation, but blinding of outcome assessors and statisticians is intended to mitigate this bias.

Design

Study Type: Multicentre, prospective, open-label, blinded-endpoint, randomized controlled trial.

Randomization: 1

Blinding: Outcome assessors and statistical analysts will be unaware of group allocation.

Enrollment Period: The first patient was enrolled on August 1, 2023.

Follow-up Duration: 90 days.

Centers: 28

Countries: China

Sample Size: 324

Analysis: Intention-to-treat (ITT) principle for the full analysis set (FAS). The difference in the proportion of 90-day mRS 0-1 will be presented as the rate difference and its 95% CI. Binary logistic regression analysis will be used for sensitivity analysis, adjusted for age, sex, center, and whether IVT was administered before MT. Interim analysis will be performed after 162 participants complete the 90-day follow-up.

Inclusion Criteria

  • Aged 18 years or older.
  • Clinical diagnosis of acute ischemic stroke (AIS).
  • Time from symptom onset to randomization within 24 hours.
  • CTA or MRA confirmed occlusion of the intracranial segment of the internal carotid artery (ICA), or M1 or M2 segment of the middle cerebral artery.
  • Stable expanded Thrombolysis in Cerebral Infarction (eTICI) score of 2b50-3 on angiography after mechanical thrombectomy (MT).
  • Baseline National Institute of Health Stroke Scale (NIHSS) score of 6-25.
  • Non-contrast CT/Diffusion Weighted Imaging (DWI)-MRI Alberta Stroke Program Early CT Score (ASPECTS) >6.
  • Prestroke mRS score ≤1, or mRS >1 but not related to neurological disease.
  • Signed informed consent.

Exclusion Criteria

  • Contraindication to recombinant human tissue plasminogen activator (except time to therapy).
  • Planned use of dual antiplatelet therapy within the first 24 hours after MT.
  • Angiographic evaluation showing dissection, severe stenosis or complete occlusion of the carotid artery requiring the use of stents.
  • Suspected cerebral vasculitis.
  • Pregnancy or breastfeeding.
  • Participation in other clinical trials.
  • Preoperative intracranial hemorrhage confirmed by cranial CT or MRI.
  • Known genetic or acquired bleeding disposition with anticoagulation factor deficiency.
  • Coagulation disorder with INR >1.7 or use of new oral anticoagulants within 48 hours.
  • Platelet count <50x10^9/L.
  • Suspected vascular occlusion due to infective endocarditis.
  • Known severe renal insufficiency with glomerular filtration rate <30 mL/min or blood creatinine >220 µmol/L.
  • Severe allergy to contrast.
  • Suspected aortic dissection.
  • Previous parenchymal organ surgery or biopsy in the last 1 month.
  • Any active or recent bleeding in the last 1 month.
  • Systolic blood pressure (SBP) >185mmHg or diastolic blood pressure (DBP) >110mmHg refractory to treatment.
  • Anticipated life expectancy <6 months.
  • Any other condition that makes the patient unsuitable or may impose a significant risk.

Baseline Characteristics

CharacteristicControlActive

Arms

FieldExperimental GroupControl
InterventionIntra-arterial alteplase (0.225 mg/kg, max 20 mg) after mechanical thrombectomy (MT), along with standard medical treatment.Standard medical treatment alone after the MT procedure.
DurationIntra-arterial alteplase infusion will be stopped 15 minutes after it begins to assess the eTICI score.Continues throughout the study period.

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Proportion of patients with a 90-day modified Rankin scale (mRS) score of 0-1.Primary40.4% (based on the CHOICE study, a previous trial).Expected 16% improvement over the control group.24.40%
Change in infarct core volume from baseline to day 7±1 or discharge.Secondary
Volume of Tmax>6s on CT perfusion (CTP) imaging from baseline to 24±12 hours.Secondary
Proportions of mRS scores 0-2 and 0-3 at 90 days.Secondary
Shift analysis of 90-day mRS.Secondary
Proportion of patients with NIHSS 0-1 or ≥10 points reduction at 48 hours.Secondary
Quality of life at 90 days measured by EuroQoL 5-Dimensions 5-Level.Secondary
Symptomatic intracranial hemorrhage (sICH)Adverse
Any intracranial hemorrhage (ICH)Adverse
Mortality within 90 daysAdverse

Subgroup Analysis

Preplanned subgroup analyses will be performed based on age (18-65 vs. ≥66 years), IVT before MT (with or without), stroke severity (NIHSS <16 vs. ≥16), culprit vessel (ICA vs. MCA), baseline glucose level, baseline ASPECTS, and number of MT manoeuvres.

Criticisms

  • The 16% superiority margin used for sample size estimation may be overly optimistic, potentially leading to an underpowered study if the actual effect size is smaller.
  • The study's focus on a Chinese population may limit the generalizability of the findings to other ethnic groups or regions.
  • The open-label design could introduce bias, despite the use of blinded outcome adjudicators.

Funding

STI 2030 Major Projects (2022ZD0211600), National Natural Science Foundation of China (81925031, 82330099, 82371369, 82304120), Key-Area Research and Development Program of Guangdong Province (2023B0303040003), Science and Technology Program of Guangzhou (2023A03J0708), Sun Yat-sen Memorial Hospital Clinical Research 5010 Program (SYS-50102-202302, SYS-5010-202402), Sun Yat-sen Pilot Scientific Research Fund (SYSQH-II-2024-04), and Shenzhen Key Medical Discipline Construction Fund (SZXK074).

Based on: PEARL (BMJ Open, 2025)

Authors: Xinguang Yang, Xiongjun He, Dong Pan, ..., Yamei Tang

Citation: BMJ Open 2024:14:e091059. doi:10.1136/bmjopen-2024-091059

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