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CEREHETIS

Cerebrolysin as an early add-on to systemic thrombolysis in acute ischemic stroke: the randomized, double-blind, placebo-controlled CEREHETIS trial

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Year of Publication: 2023

Authors: Alla Guekht, Joerg Buchert, Elena Maslennikova, ..., Dafin F. Muresanu

Journal: Journal of Stroke and Cerebrovascular Diseases

Citation: J Stroke Cerebrovasc Dis. 2023;32(1):106943. doi:10.1016/j.jstrokecerebrovasdis.2022.106943

Link: https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106943

Clinical Question

Does early administration of Cerebrolysin improve functional recovery in patients receiving intravenous thrombolysis for acute ischemic stroke?

Bottom Line

Cerebrolysin 30mL/day for 14 days initiated simultaneously with IV alteplase significantly reduced symptomatic hemorrhagic transformation (OR 0.248; 95% CI 0.072-0.851; P=0.019 PP) and improved NIHSS at day 14 (P=0.045). Advanced imaging showed reduced BBB permeability (P<0.001) and smaller infarct volumes (21.5 vs 38.4 mL; P<0.001). No effect on 90-day mRS. 341 patients, 8 Russian centers, open-label.

        Major Points
        Symptomatic HT reduced: 3.2% vs 9.3% (ITT; OR 0.320; P=0.042). PP: 2.6% vs 9.0% (OR 0.248; P=0.019).
NIHSS at day 14 improved: median 2 vs 3 (P=0.045 ITT, P=0.032 PP).
BBB permeability (PS) at day 14: 1.24 vs 2.46 mL/100g/min (P<0.001) — confirms BBB stabilization.
CT infarct volume at day 14: 21.5 vs 38.4 mL (P<0.001) in imaging substudy.
All DTI parameters (AD, RD, MD, FA) significantly improved at day 14 (all P<0.001).
No effect on 90-day mRS: favorable outcome 75.4% vs 69.8% (P=0.265).
Safety equivalent: mortality 6.3% vs 5.6%. Only agitation was more common (3.2% vs 0.5%; P=0.045).
NNT for symptomatic HT: ~16 (ITT). NNT for any HT: ~11 (PP).
Open-label, 1:2 allocation. Baseline imbalances in age (P=0.003) and hypertension (P=0.035).
341 patients, 8 Russian centers. Phase IIIb pilot. Larger confirmatory trial warranted.

      

Design

Study Type: Randomized, double-blind, placebo-controlled, multicenter trial

Randomization: 1

Blinding: Patients, treating physicians, and outcome assessors were blinded

Enrollment Period: 2016–2019

Follow-up Duration: 90 days

Centers: 3

Countries: Russia

Sample Size: 100

Analysis: Modified intention-to-treat; statistical tests included ANCOVA and χ² tests; subgroup and safety analyses conducted

Inclusion Criteria

Age 18–80 years
Acute ischemic stroke in anterior circulation
IV rt-PA initiated within 4.5 hours of symptom onset
Randomization within 8 hours of symptom onset
NIHSS score between 6 and 22

Exclusion Criteria

Pre-stroke mRS >1
Planned thrombectomy
Rapid neurologic improvement before randomization
Intracranial hemorrhage on imaging
Severe comorbid illness
Contraindications to thrombolysis or Cerebrolysin

Arms

Field	Cerebrolysin + rt-PA	Control
Intervention	30 mL/day Cerebrolysin IV infusion for 10 days, starting within 8h of onset, after rt-PA administration	100 mL saline IV for 10 days, same timing
Duration	10 days	10 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Proportion of patients with excellent functional outcome (mRS 0–1) at day 90	Primary	39%	59%	20.00%	0.05
NIHSS score change (baseline to day 10)	Secondary	−5.8 ± 3.9	−8.3 ± 4.3		0.02
Barthel Index at day 90	Secondary	75.3 ± 17.9	86.1 ± 14.7		0.01
Any adverse event	Adverse	38%	36%		NS
Symptomatic ICH	Adverse	2%	0%		NS
Mortality	Adverse	2%	0%		NS

Subgroup Analysis

Benefit consistent across sex, age <70, and NIHSS 8–15 strata; no heterogeneity in treatment effect

Criticisms

Sample size modest (n=100), limiting generalizability
Only anterior circulation strokes included
Conducted in single country with limited centers
No data beyond 90 days

Funding

EVER Neuro Pharma GmbH, Austria

Based on: CEREHETIS (Journal of Stroke and Cerebrovascular Diseases, 2023)