Cerebrolysin and the optimal timing of anticoagulation resumption in stroke: combined post hoc survival analysis of the CEREHETIS trial

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OBJECTIVE

To evaluate the effect of Cerebrolysin on hazard dynamics of hemorrhagic transformation (HT) and identify optimal anticoagulation therapy (AT) resumption timing in stroke patients, stratified by the Hemorrhagic Transformation Index (HTI).

MATERIAL AND METHODS

A post hoc survival analysis of the CEREHETIS trial (ISRCTN87656744) included patients with middle cerebral artery infarctions. The intervention group (IG, n=91) received Cerebrolysin with intravenous thrombolysis (IVT) and standard care, while the control group (CG, n=147) received IVT and standard care alone. Additionally, a validation cohort (VC, n=248) from an observational study was analyzed. Patients were stratified into low-risk (HT=0), high-risk (HTI=1—4), and very-high-risk (HTI=5—8, VC only) groups. Symptomatic HT and any HT within 14 days post-stroke were defined as failure events. Hazard dynamics were modeled using a Gompertz parametric survival approach, with a hazard threshold (0.6% per day) estimating safe AT resumption timing.

RESULTS

Cerebrolysin significantly reduced risk of symptomatic HT (HR 0.245; 95% CI 0.072—0.837; p=0.02) and any HT (HR 0.543; 95% CI 0.297—0.991; p=0.032). The compounding effect peaked on day 1 and persisted through days 7—10 in very-high-risk patients (HTI=5—8). In high-risk patients (HTI=1—4), Cerebrolysin mitigated the compounding effect and reduced hazard levels to the threshold by day 2, compared to days 3—5 in the CG and VC. The hazardous period extended to day 10 in HTI=5—8. In low-risk patients (HTI=0), hazard levels remained below the threshold from day 1, with no measurable impact of Cerebrolysin on HT.

CONCLUSION

AT may be safely resumed within 48 h in low-risk patients (HTI=0), on days 3—5 in high-risk patients (HTI=1—4), and on day 10 in very-high-risk patients (HTI=5—8) without symptomatic HT. Cerebrolysin mitigates the compounding effect, reduces HT risk, and facilitates earlier, safer AT resumption in high-risk patients (HTI=1—4) by day 2 post-stroke, supporting its role in personalized stroke management.

Keywords:

Cerebrolysin

hemorrhagic transformation

stroke

intravenous thrombolysis

anticoagulation timing

Authors:

Kalinin M.N.

Kazan State Medical University;
Interregional Clinical Diagnostic Center

ORCID: 0000-0002-3664-6888

Khasanova D.R.

Kazan State Medical University;
Interregional Clinical Diagnostic Center

ORCID: 0000-0002-8825-2346

Received:

10.01.2025

Accepted:

13.01.2025

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