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

Kalinin M.N.; Khasanova D.R.

doi:https://doi.org/10.17116/jnevro202512503277

Close metadata

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

Close metadata

References:

Tsivgoulis G, Katsanos AH, Sandset EC, et al. Thrombolysis for acute ischaemic stroke: current status and future perspectives. Lancet Neurol. 2023;22(5):418-429. https://doi.org/10.1016/S1474-4422(22)00519-1
Raha O, Hall C, Malik A, et al. Advances in mechanical thrombectomy for acute ischaemic stroke. BMJ medicine. 2023;2(1):e000407. https://doi.org/10.1136/BMJMED-2022-000407
Otsu Y, Namekawa M, Toriyabe M, et al. Strategies to prevent hemorrhagic transformation after reperfusion therapies for acute ischemic stroke: A literature review. J Neurol Sci. 2020;419:117217. https://doi.org/10.1016/J.JNS.2020.117217
Lang W, Stadler CH, Poljakovic Z, et al. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke. 2013;8(2):95-104. https://doi.org/10.1111/J.1747-4949.2012.00901.X
Poljakovic Z, Supe S, Ljevak J, et al. Efficacy and safety of Cerebrolysin after futile recanalisation therapy in patients with severe stroke. Clin Neurol Neurosurg. 2021;207:106767. https://doi.org/10.1016/J.CLINEURO.2021.106767
Khasanova DR, Kalinin MN. Cerebrolysin as an Early Add-on to Reperfusion Therapy: Risk of Hemorrhagic Transformation after Ischemic Stroke (CEREHETIS), a prospective, randomized, multicenter pilot study. BMC Neurol. 2023;23:121. https://doi.org/10.1186/S12883-023-03159-W
Khasanova DR, Kalinin MN. Effects of simultaneous use of Cerebrolysin and alteplase on hemorrhagic transformation of brain infarction and functional outcome in stroke patients: CEREHETIS, a randomized, multicenter pilot trial. S.S. Korsakov Journal of Neurology and Psychiatry. 2023;123(8-2):60-69. (In Russ.). https://doi.org/10.17116/JNEVRO202312308260
Kalinin MN, Khasanova DR. Heterogeneous treatment effects of Cerebrolysin as an early add-on to reperfusion therapy: post hoc analysis of the CEREHETIS trial. Front Pharmacol. 2024;14:1288718. https://doi.org/10.3389/FPHAR.2023.1288718
Kalinin MN, Khasanova DR. Cerebrolysin as an early add-on to reperfusion therapy: heterogeneous treatment effect analysis in ischemic stroke patients with varying risk of hemorrhagic transformation. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;124(3-2):55-66. (In Russ.). https://doi.org/10.17116/JNEVRO202412403255
Masliah E, Díez-Tejedor E. The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs Today (Barc). 2012;48(Suppl A):3-24. https://doi.org/10.1358/DOT.2012.48(SUPPL.A).1739716
Zhang C, Chopp M, Cui Y, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res. 2010;88(15):3275-3281. https://doi.org/10.1002/JNR.22495
Teng H, Li C, Zhang Y, et al. Therapeutic effect of Cerebrolysin on reducing impaired cerebral endothelial cell permeability. Neuroreport. 2021;32(5):359-366. https://doi.org/10.1097/WNR.0000000000001598
Guekht A, Vester J, Heiss WD, et al. Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials. Neurol Sci. 2017;38(10):1761-1769. https://doi.org/10.1007/S10072-017-3037-Z
Bornstein NM, Guekht A, Vester J, et al. Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials. Neurol Sci. 2018;39(4):629-640. https://doi.org/10.1007/S10072-017-3214-0
Wilson D, Ambler G, Banerjee G, et al. Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: Multicentre cohort study. J Neurol Neurosurg Psychiatry. 2019;90(3):320-325. https://doi.org/10.1136/jnnp-2018-318890
Sharobeam A, Lin L, Lam C, et al. Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study. Stroke Vasc Neurol. 2024;9(1):30-37. https://doi.org/10.1136/SVN-2023-002357
Fischer U, Koga M, Strbian D, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med. 2023;388(26):2411-2421. https://doi.org/10.1056/NEJMOA2303048
Kalinin MN, Khasanova DR, Ibatullin MM. Possible timing for anticoagulation therapy initiation in ischemic stroke patients with atrial fibrillation: further analysis of the hemorrhagic transformation index. Neurology, Neuropsychiatry, Psychosomatics. 2019;11(2):12-21. (In Russ.). https://doi.org/10.14412/2074-2711-2019-2-12-21
Kalinin M, Khasanova D. Cerebrolysin, Hemorrhagic Transformation, and Anticoagulation Timing after Reperfusion Therapy in Stroke: Secondary Analysis of the CEREHETIS Trial. Res Sq. Published online 2024. https://doi.org/10.21203/rs.3.rs-5101232/v1
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. https://doi.org/10.1056/NEJMOA0804656
Merwick Á, Werring D. Posterior circulation ischaemic stroke. BMJ. 2014;348:g3175. https://doi.org/10.1136/BMJ.G3175
Sung SF, Chen CH, Chen YW, et al. Predicting symptomatic intracerebral hemorrhage after intravenous thrombolysis: stroke territory as a potential pitfall. J Neurol Sci. 2013;335(1-2):96-100. https://doi.org/10.1016/J.JNS.2013.08.036
Kalinin MN, Khasanova DR, Ibatullin MM. The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke. BMC Neurol. 2017;17:177. https://doi.org/10.1186/S12883-017-0958-3
de Andrade JBC, Mohr JP, Ahmad M, et al. Accuracy of predictive scores of hemorrhagic transformation in patients with acute ischemic stroke. Arq Neuropsiquiatr. 2022;80(5):455-461. https://doi.org/10.1590/0004-282X-ANP-2021-0091
Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1588. https://doi.org/10.1056/NEJM199512143332401
Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612-1676. https://doi.org/10.1093/EUROPACE/EUAB065
Syriopoulou E, Wästerlid T, Lambert PC, Andersson TML. Standardised survival probabilities: a useful and informative tool for reporting regression models for survival data. Br J Cancer. 2022;127(10):1808-1815. https://doi.org/10.1038/S41416-022-01949-6
Royston P. Estimating the treatment effect in a clinical trial using difference in restricted mean survival time. Stata J. 2015;15(4):1098-1117. https://doi.org/10.1177/1536867X1501500409
Hertz-Picciotto I, Rockhill B. Validity and Efficiency of Approximation Methods for Tied Survival Times in Cox Regression. Biometrics. 1997;53(3):1151. https://doi.org/10.2307/2533573
Newson RB. Attributable and unattributable risks and fractions and other scenario comparisons. Stata J. 2013;13(4):672-698. https://doi.org/10.1177/1536867X1301300402
Yang Z, Yin G. An alternative approach for estimating the number needed to treat for survival endpoints. PLoS One. 2019;14(10):23-29. https://doi.org/10.1371/JOURNAL.PONE.0223301
Clarke D, Romano JP, Wolf M. The Romano–Wolf multiple-hypothesis correction in Stata. Stata J. 2020;20(4):812-843. https://doi.org/10.1177/1536867X20976314
Alrohimi A, Rose DZ, Burgin WS, et al. Risk of hemorrhagic transformation with early use of direct oral anticoagulants after acute ischemic stroke: A pooled analysis of prospective studies and randomized trials. Int J Stroke. 2023;18(7):864-872. https://doi.org/10.1177/17474930231164891
Suzuki K, Aoki J, Sakamoto Y, et al. Low risk of ICH after reperfusion therapy in acute stroke patients treated with direct oral anti-coagulant. J Neurol Sci. 2017;379:207-211. https://doi.org/10.1016/J.JNS.2017.06.004
Kimura S, Toyoda K, Yoshimura S, et al. Practical “1-2-3-4-Day” Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study. Stroke. 2022;53(5):1540-1549. https://doi.org/10.1161/STROKEAHA.121.036695
Seiffge DJ, Cancelloni V, Räber L, et al. Secondary stroke prevention in people with atrial fibrillation: treatments and trials. Lancet Neurol. 2024;23(4):404-417. https://doi.org/10.1016/S1474-4422(24)00037-1
Palaiodimou L, Stefanou MI, Katsanos AH, et al. Timing of oral anticoagulants initiation for atrial fibrillation after acute ischemic stroke. Eur Stroke J. 2024;9(4):885-895. https://doi.org/10.1177/23969873241251931
Werring DJ, Dehbi HM, Ahmed N, et al. Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS):a multicentre, blinded-endpoint, phase 4, randomised controlled trial. Lancet. 2024;404(10464):1731-1741. https://doi.org/10.1016/S0140-6736(24)02197-4
Paciaroni M, Agnelli G, Ageno W, Caso V. Timing of anticoagulation therapy in patients with acute ischaemic stroke and atrial fibrillation. Thromb Haemost. 2016;116(3):410-416. https://doi.org/10.1160/TH16-03-0217
Tanaka K, Koga M, Lee KJ, et al. Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke. Stroke. 2020;51(4):1150-1157. https://doi.org/10.1161/STROKEAHA.119.027275
Seiffge DJ, De Marchis GM, Koga M, et al. Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Ann Neurol. 2020;87(5):677-687. https://doi.org/10.1002/ANA.25700
Meinel TR, Wilson D, Gensicke H, et al. Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurol. 2023;80(3):233-243. https://doi.org/10.1001/JAMANEUROL.2022.4782
Ghannam M, Almajali M, Galecio-Castillo M, et al. Intravenous Thrombolysis for Acute Ischemic Stroke in Patients With Recent Direct Oral Anticoagulant Use. J Am Heart Assoc. 2023;12(24):e031669. https://doi.org/10.1161/JAHA.123.031669
Behnoush AH, Khalaji A, Bahiraie P, Gupta R. Meta-analysis of outcomes following intravenous thrombolysis in patients with ischemic stroke on direct oral anticoagulants. BMC Neurol. 2023;23(1):34-39. https://doi.org/10.1186/S12883-023-03498-8
Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021;6(1):1-63. https://doi.org/10.1177/2396987321989865
Hong JM, Kim DS, Kim M. Hemorrhagic Transformation After Ischemic Stroke: Mechanisms and Management. Front Neurol. 2021;12(7):45-49. https://doi.org/10.3389/FNEUR.2021.703258
Spronk E, Sykes G, Falcione S, et al. Hemorrhagic Transformation in Ischemic Stroke and the Role of Inflammation. Front Neurol. 2021;12:661955. https://doi.org/10.3389/FNEUR.2021.661955
Wang X, Tsuji K, Lee SR, et al. Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. Stroke. 2004;35(11 Suppl 1):2726-2730. https://doi.org/10.1161/01.STR.0000143219.16695.AF
Kelly MA, Shuaib A, Todd KG. Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. Exp Neurol. 2006;200(1):38-49. https://doi.org/10.1016/J.EXPNEUROL.2006.01.032
Veinbergs I, Mante M, Mallory M, Masliah E. Neurotrophic effects of Cerebrolysin in animal models of excitotoxicity. J Neural Transm Suppl. 2000;59:273-280. https://doi.org/10.1007/978-3-7091-6781-6_29
Guan X, Wang Y, Kai G, et al. Cerebrolysin Ameliorates Focal Cerebral Ischemia Injury Through Neuroinflammatory Inhibition via CREB/PGC-1α Pathway. Front Pharmacol. 2019;10:1245. https://doi.org/10.3389/FPHAR.2019.01245
Dammavalam V, Lin S, Nessa S, et al. Neuroprotection during Thrombectomy for Acute Ischemic Stroke. Int J Mol Sci. 2024;25(2):45-48. https://doi.org/10.3390/IJMS25020891
Mazighi M, Köhrmann M, Lemmens R, et al. Safety and efficacy of platelet glycoprotein VI inhibition in acute ischaemic stroke (ACTIMIS):a randomised, double-blind, placebo-controlled, phase 1b/2a trial. Lancet Neurol. 2024;23(2):157-167. https://doi.org/10.1016/S1474-4422(23)00427-1
Hill MD, Goyal M, Menon BK, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1). Lancet. 2020;395(10227):878-887. https://doi.org/10.1016/S0140-6736(20)30258-0
Strilciuc S, Vécsei L, Boering D, et al. Safety of cerebrolysin for neurorecovery after acute ischemic stroke: A systematic review and meta-analysis of twelve randomized-controlled trials. Pharmaceuticals. 2021;14(12):1297. https://doi.org/10.3390/PH14121297
The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke. 1997;28(11):2109-2118. https://doi.org/10.1161/01.STR.28.11.2109
Muscari A, Faccioli L, Lega MV, et al. Predicting hemorrhagic transformation and its timing from maximum cerebral lesion diameter in nonlacunar ischemic strokes. Brain Behav. 2020;10(1):33-38. https://doi.org/10.1002/BRB3.1497
Kalinin MN, Khasanova DR, Ibatullin MM. A comprehensive assessment of brain perfusion data in patients with acute ischemic stroke for prediction of hemorrhagic transformation. S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(3-2):24-36. (In Russ.). https://doi.org/10.17116/JNEVRO201911903224
Morsi RZ, Elfil M, Ghaith HS, et al. Endovascular thrombectomy for large ischemic strokes. J Neurol Sci. 2024;460:123003. https://doi.org/10.1016/J.JNS.2024.123003
Staszewski J, Stȩpień A, Piusińska-Macoch R, et al. Efficacy of Cerebrolysin Treatment as an Add-On Therapy to Mechanical Thrombectomy in Patients With Acute Ischemic Stroke Due to Large Vessel Occlusion. Front Neurol. 2022;13:910697. https://doi.org/10.3389/FNEUR.2022.910697