Cerebrolysin, Hemorrhagic Transformation, and Anticoagulation Timing after Reperfusion Therapy in Stroke: Secondary Analysis of the CEREHETIS Trial

doi:10.21203/rs.3.rs-5101232/v1

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Research Article

Cerebrolysin, Hemorrhagic Transformation, and Anticoagulation Timing after Reperfusion Therapy in Stroke: Secondary Analysis of the CEREHETIS Trial

https://doi.org/10.21203/rs.3.rs-5101232/v1

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Background

Evidence supports Cerebrolysin’s efficacy in reducing hemorrhagic transformation (HT), but its impact on the timing of resuming anticoagulation therapy in stroke patients remains unclear.

Methods

A post hoc survival analysis of the CEREHETIS trial (ISRCTN87656744) was conducted. Patients with middle cerebral artery infarction (n = 238) were categorized into low-risk (HTI = 0) and high-risk (HTI > 0) groups based on HTI scores. The 14-day follow-up included any HT and symptomatic HT as failure events. Hazard deceleration (HD) curves were generated using the Gompertz model to estimate changes in the hazard function over time. The inception point, defined as when the HD curve dropped below the 5% threshold, indicated a constant hazard function. Timing of restarting anticoagulation therapy was inferred from the inception points using the HD curves and the lower limit of their 95% confidence intervals (CI).

Results

In the HTI > 0 cohort, Cerebrolysin reduced the risk of symptomatic HT and any HT, with hazard ratios of 0.245 (95% CI 0.072–0.837; p = 0.020) and 0.543 (95% CI 0.297–0.991; p = 0.032), respectively. Inception points for resuming anticoagulation therapy occurred on days 2–3 for the Cerebrolysin group and days 4–5 for the control group. In the HTI = 0 cohort, Cerebrolysin was ineffective, with inception points for both groups at the two-day mark.

Conclusion

Cerebrolysin may reduce the risk of HT and allow for a 1-2-day earlier resumption of anticoagulation therapy in patients at high risk of HT. However, its benefit is limited in those with initially low HT risk.

Cerebrolysin

Hemorrhagic Transformation

Stroke

Reperfusion Therapy

Anticoagulation Timing

Recent advances in reperfusion therapy, including third-generation thrombolytic agents and endovascular thrombectomy, have significantly transformed stroke care [1, 2]. Despite these advancements, optimizing the outcome of intravenous thrombolysis (IVT) with alteplase—currently the gold-standard treatment for acute ischemic stroke—remains a major focus [3]. Combining multimodal cytoprotective agents like Cerebrolysin with IVT has emerged as a promising strategy to enhance penumbra survival, mitigate reperfusion injury, and reduce the risk of hemorrhagic transformation (HT) [4–9].

Cerebrolysin is a purified porcine brain derivative containing low-molecular-weight neuropeptides and free amino acids, which function similarly to endogenous neurotrophic factors in protecting and repairing neurovascular units [10–12]. Clinical trials and meta-analyses suggest that Cerebrolysin promotes early post-stroke recovery, reduces neurological deficits, and has a favorable safety and tolerability profile [4, 13, 14]. Our original CEREHETIS study [6, 7] and subsequent analyses [8, 9] reported that Cerebrolysin, in conjunction with IVT, is safe, reduces the HT rate, and improves functional outcomes in stroke patients with moderate to high HT risk as estimated upon admission.

However, it remains unclear how the anti-HT effects of Cerebrolysin interact with time and affect the timing of restarting anticoagulation therapy in stroke patients with atrial fibrillation (AF). This is crucial because determining the optimal timing for resuming anticoagulation is challenging despite ample research [15–17]. Clinicians often face a delicate dilemma: initiating anticoagulation too early may increase the risk of intracranial bleeding, while delaying it can heighten the likelihood of recurrent ischemic events.

To address these issues, we conducted a post hoc survival analysis of the CEREHETIS trial to evaluate the HT survival/hazard function and the time-related effects of Cerebrolysin treatment in patients with varying predicted HT risks within a two-week period from admission. We also used these findings to establish the timing for restarting anticoagulation based on hazard analysis.

CEREHETIS was a prospective, randomized, open-label, active control, multicenter, parallel-group, phase IIIb pilot study (trial registration number: ISRCTN87656744). The protocol, patient inclusion and exclusion criteria, and the original results have been published previously [6, 7].

Enrollment took place across eight centers in Russia. Each eligible patient was randomly assigned to either the Cerebrolysin group or the control group. Both arms received a standard intravenous dose of 0.9 mg/kg alteplase (Actilyse®, Boehringer Ingelheim GmbH, Germany) within 4.5 h of symptom onset. Of this dose, 10% was administered as a bolus, while the remainder was infused over 60 minutes, with the maximum dosage not exceeding 90 mg. Patients in the intervention group additionally received 30 mL of Cerebrolysin® (EVER Pharma GmbH, Austria) mixed in 100 mL of normal saline, infused intravenously via a separate line over 20 minutes. This treatment was initiated simultaneously with IVT and continued once daily for 14 consecutive days.

In patients with non-valvular AF, secondary stroke prevention with a non-vitamin K antagonist oral anticoagulant (NOAC) was initiated between days 3 and 6, following the 1-3-6-12-day rule [18], regardless of the treatment group. Further references to the ‘timing of restarting anticoagulation therapy’ will specifically address the time frame for resuming NOACs in stroke patients with non-valvular AF.

Failure events were defined as any HT and symptomatic HT. These events were verified by scheduled follow-up computed tomography scans at 24 h, on days 7 and 14, or at any time upon a clinician’s request. The time scale was measured in days from admission, with HT occurring within 24 h after IVT credited to day 1. Symptomatic HT was defined according to the ECASS III trial as any extravascular blood in the brain or within the cranium associated with clinical deterioration, indicated by an increase of four points or more on the National Institutes of Health Stroke Scale (NIHSS), or leading to death and identified as the predominant cause of neurological deterioration [19].

The analysis period was limited to 14 consecutive days, with right-censoring applied to patients who did not experience failure. Drop-out participants were censored on the day of their exit. Subjects with any HT and symptomatic HT were considered to have failed on the day HT was confirmed.

Study measurements

The current study used the same cohort as our previous research [8, 9]. We selected patients with middle cerebral artery (MCA) infarction from the intention-to-treat population of the CEREHETIS trial. MCA stroke patients were chosen for their anatomical homogeneity, which helped reduce variability in treatment effects due to differences between anterior and posterior circulation. Findings from other studies [20, 21] indicated that certain HT risk assessment tools were less effective for posterior circulation strokes, supporting our focus on MCA stroke patients. Our previous research established the Hemorrhagic Transformation Index (HTI) score as the most reliable measure for estimating HT risk upon admission in this cohort, and patients with an HTI score greater than 0 derived the greatest benefit from Cerebrolysin treatment [8, 9]. Accordingly, the HTI score was calculated for each eligible patient based on admission data and divided into two subgroups: HTI = 0 (low HT risk) and HTI > 0 (high HT risk).

The HTI score was defined according to the original source [22] as follows: Alberta Stroke Program Early Computed Tomography Score (ASPECTS): 10–7 = 0, 6–5 = 1, 4–3 = 2, 2–0 = 3; NIHSS: 0–11 = 0, 12–17 = 1, 18–23 = 2, > 23 = 3; hyperdense MCA sign: yes = 1; AF on ECG upon admission: yes = 1. The score ranged from 0 to 8, with each point increment corresponding to an increased probability of HT. Although this tool was developed and externally validated [23] to predict any HT in MCA stroke patients regardless of IVT, it also demonstrated efficacy in predicting IVT-related symptomatic HT [8, 9].

Statistical analysis

Data analysis was performed using Stata/SE v.17.0 (StataCorp LLC, USA). Descriptive statistics included the median (M) with the interquartile range (IQR) for non-normally distributed continuous variables and percentages for categorical variables. Group comparisons of baseline characteristics were made using the Mann–Whitney U test for continuous variables and Pearson’s χ² test for categorical variables.

Survival analysis is used to analyze the expected duration of time until one or more events occur. The following terms are relevant in this context:

Survival function S(t): The probability that a patient will not experience HT by a certain time point t.
Restricted mean survival time (RMST): The mean survival time up to a specific time horizon t*. In clinical trials, the treatment effect can be defined as the difference in RMST between treatment arms at time t*. RMST is estimated by calculating the area under the survival curve between 0 and t* [24, 25].
Hazard function h(t): The instantaneous rate at which HT occurs, given that no previous events have occurred.
Hazard acceleration: The rate of change of the hazard function with respect to time t. As the probability of HT decreases over time [26], this acceleration becomes negative and is referred to as hazard deceleration (HD).
Inception point: The moment when the risk of HT is no longer imminent, and the competing risk of recurrent ischemic events predominates, allowing for the safe resumption of anticoagulation. This can be defined parametrically as the point in time t when HD approaches 0 and the hazard function becomes constant, or semiparametrically as the time point when the Cox time-dependent (TD) hazard ratio (HR) equals 1. The period before the inception point is called the hazardous period.
Standardized curve: The average of the predicted curves generated for each observation in the dataset [24].
Difference in the curves: The contrast between two hypothetical scenarios: one where all patients receive Cerebrolysin treatment and one where none do [24]. The difference in survival is termed the absolute risk reduction (ARR).

The survival function was adjusted for Cerebrolysin treatment and dichotomized HTI score (HTI = 0 and HTI > 0), followed by nonparametric, semiparametric, and parametric analyses.

Nonparametric analysis: Kaplan–Meier survival curves were generated and compared using the log-rank test. If the proportional hazard (PH) assumption was violated, a combined test with 5,000 permutations was additionally used to validate the results [27].
Semiparametric analysis: The Cox PH model was fitted, and tied failures were handled using the Efron method for its superior performance [28]. The PH assumption was evaluated using graphical diagnostics and the Schoenfeld residuals test. If violated, a Cox TD model with time-varying covariates was fitted, and the TD HRs with 95% confidence intervals (CI) were plotted.
Parametric analysis: Sequential fitting of Gompertz, exponential, log-logistic, lognormal, Royston–Parmar, and Weibull models was conducted. Model selection was based on the Akaike and Bayesian information criteria and the similarity of the Cox–Snell residuals vs. Nelson–Aalen cumulative hazard plots to the Cox PH graph. Ancillary parameters were included to refine the hazard shape, and standardized survival, hazard, and RMST curves were generated [24]. Goodness-of-fit statistics were evaluated using various post-estimation tests.

The effect of Cerebrolysin treatment on HT was assessed parametrically using HR, population attributable fraction, ARR, number needed to treat (NNT), and RMST difference [24, 25, 29]. The NNT calculation was based on the ARR formula [30]. HR p-values were adjusted for multiple hypothesis testing using the Romano–Wolf method with 1,000 bootstrap replications [31].

HD was derived from the derivative of the standardized hazard function with corresponding 95% CIs and transformed into an absolute value: HD = |h′(t)|. The hazardous period and inception points were determined from HD and Cox TD HR curves, considering their means and the lower bounds of their 95% CIs.

The threshold HD value, below which the hazard function is considered constant over time, was defined for the most vulnerable subgroup (control patients with HTI > 0). This threshold was assumed to be 5% of the highest HD value within the lower limit of the 95% CI.

The Hausman specification test was used to compare the coefficients of parametric and semiparametric models to assess whether there was a significant difference between them. If the test indicated no significant difference (p ≥ 0.05), the more efficient model was chosen for inferring the timing of restarting anticoagulation, as it was assumed to be consistent. However, if a significant difference was detected (p < 0.05), the consistent model was preferred to avoid potential bias in estimating the timing of resuming anticoagulation therapy. The Stata code and raw data used in this study are provided in the Supplementary Material.

Although the intention-to-treat population of the CEREHETIS trial comprised 341 subjects, only 238 met the inclusion criteria (Fig. 1). Just over a quarter of the eligible individuals had AF, but none experienced recurrent stroke during the follow-up period. More than half of the patients were in the HTI > 0 subgroup, with the upper range of the HTI score limited to 4 out of 8 possible points. At baseline, patients in the Cerebrolysin arm were slightly younger and had fewer cases of previous stroke (Table 1). However, this covariate imbalance did not affect failure events, even after adjustment using both semiparametric and parametric analyses.

Table 1

Baseline characteristics at admission (n = 238).
	Cerebrolysin, n = 91	Control, n = 147	p-Value
Age, yr (M, IQR)	64 (56–72)	69 (61–79)	0.006
Sex, male, n (%)	53 (58.2)	78 (53.1)	0.435
NIHSS (M, IQR)	11 (7–14)	11 (7–15)	0.687
ASPECTS (M, IQR)	10 (9–10)	10 (9–10)	0.668
Hyperdense MCA sign, n (%)	6 (6.59)	6 (4.08)	0.389
Atrial fibrillation, history, n (%)	27 (29.7)	33 (22.5)	0.212
Atrial fibrillation, on ECG, n (%)	25 (27.5)	38 (25.9)	0.783
Diabetes mellitus, n (%)	17 (18.7)	22 (15.0)	0.452
Hypertension, n (%)	72 (79.1)	129 (87.8)	0.074
Previous stroke, n (%)	13 (14.3)	38 (25.9)	0.035
Previous use of antiplatelet agents, n (%)	24 (26.4)	39 (26.5)	0.979
Systolic blood pressure, mm Hg (M, IQR)	150 (138–165)	150 (140–165)	0.618
Diastolic blood pressure, mm Hg (M, IQR)	90 (80–100)	90 (80–97)	0.916
Random blood sugar, mmol/L (M, IQR)	6.5 (5.5–7.8)	6.2 (5.3–7.3)	0.254
Weight, kg (M, IQR)	80 (67–90)	74 (66–85)	0.184
Onset time, min (M, IQR)	105 (80–150)	95 (65–140)	0.295
Door-to-needle time, min (M, IQR)	40 (30–60)	40 (30–60)	0.985
Stroke subtype, n (%)
Atherothrombotic	26 (28.6)	56 (38.0)	0.133
Cardioembolic	29 (31.9)	43 (29.3)	0.669
Lacunar	1 (1.1)	4 (2.7)	0.396
Other known etiology	0 (0)	1 (0.7)	0.430
Unknown etiology	35 (38.4)	43 (29.3)	0.141
Drop-out patients, n (%)	7 (7.7)	13 (8.8)	0.756
Death	6 (6.6)	11 (7.5)	0.796
Neurosurgery	1 (1.1)	1 (0.7)	0.731
Severe medical condition	0 (0)	1 (0.7)	0.430
HTI score (M, IQR)	1 (0–2)	1 (0–2)	0.655
HTI > 0, n (%)	57 (62.6)	80 (54.4)	0.213

Figure 1.

Table 1.

The nonparametric survival curves lay above the 50% survival probability due to the low incidence rate of HT, rendering the median survival time unavailable for analysis (Table 2, Fig. 2A, B). The Kaplan–Meier survival estimates were equal between the Cerebrolysin and control groups in patients with HTI = 0 (symptomatic HT: log-rank test, χ²(1) = 1.03, p = 0.311; any HT: log-rank test, χ²(1) = 0.07, p = 0.785; combined test, stochastic p = 0.9999, 95% CI 0.9992–0.9999). Conversely, a significant difference was observed in the HTI > 0 cohort (symptomatic HT: log-rank test, χ²(1) = 5.27, p = 0.022; any HT: log-rank test, χ²(1) = 4.45, p = 0.035; combined test, stochastic p = 0.021, 95% CI 0.017–0.025) (Fig. 2A, B).

Table 2

Summary of the survival data (n = 238).
Group	Symptomatic HT			Any HT
	Time at risk, d	Incidence rate	Number of patients	Time at risk, d	Incidence rate	Number of patients
HTI = 0
Control	908	0.002	67	887	0.006	67
Cerebrolysin	476	0	34	450	0.004	34
Total	1,384	0.001	101	1,337	0.005	101
HTI > 0
Control	853	0.018	80	645	0.050	80
Cerebrolysin	704	0.004	57	598	0.022	57
Total	1,557	0.012	137	1,243	0.036	137

Table 2.

Figure 2.

Further refinement with the Cox PH model indicated that Cerebrolysin treatment, adjusted for the dichotomized HTI score, significantly reduced HT probability, with a corresponding HR of 0.239 (95% CI 0.070–0.817, p = 0.022) for symptomatic HT and 0.527 (95% CI 0.289–0.962, p = 0.037) for any HT. However, the confounder violated the PH assumption (χ²(2) = 11.19, p = 0.004) and interacted with time by affecting the hazard shape of any HT, though this violation was not found for symptomatic HT (Fig. 3).

Figure 3.

The data allowed for fitting the Royston–Parmar flexible parametric model with only one degree of freedom for the restricted cubic spline function and TD effects, making it equivalent to the loglogistic, lognormal, or Weibull model depending on the chosen scale. The Gompertz model emerged as the most appropriate among the available candidates (Fig. 4), suggesting the hazard function would exponentially decline over time (Fig. 2C, D).

Figure 4.

Moreover, an ancillary γ-parameter of the dichotomized HTI score significantly adjusted the hazard shape of any HT and improved overall data fitting (Fig. 3, 4). As a result, the Gompertz standardized survival curves perfectly superimposed on the Kaplan–Meier estimates (Fig. 2A, B). Likewise, the Gompertz regression coefficients and goodness-of-fit statistics were almost identical to those of the Cox model (Fig. 3, Table 3).

Table 3

Goodness-of-fit statistics.
	Symptomatic HT		Any HT		Comments
	Cox PH model	Gompertz model	Cox PH model	Gompertz model
γ-shared frailty variance, θ	< 0.001	< 0.001	0.211	0.234*	Shared frailty among the trial centers
LR test, χ̅²(1), p-value	< 0.001, 0.500	< 0.001, > 0.999	0.95, 0.165	1.09, 0.148*	Likelihood-ratio test of θ = 0, p > 0.05
γ-frailty variance, θ	-	< 0.001	-	< 0.001*	Unshared frailty
LR test, χ̅²(1), p-value	-	< 0.001, > 0.999	-	< 0.001, > 0.999*	Likelihood-ratio test of θ = 0, p > 0.05
Link test, p-value	0.648	0.645	0.688	0.722	Test for model specification error, p > 0.05
Grønnesby–Borgan test, χ²(1), p-value	0.282, 0.596		0.162, 0.687		Omnibus goodness-of-fit test for Cox PH model, p > 0.05
Discrimination and explained variation					The higher the value, the better
Harrell’s C	0.758	0.758	0.735	0.735
Somers’ D	0.516	0.516	0.470	0.470
Royston–Sauerbrei D	2.095	2.079	1.507	1.845
Royston–Sauerbrei R²_D	0.512	0.508	0.352	0.448	> 0.30
Note: *The test settings did not allow for fitting the model with an ancillary parameter.

Table 3.

The Gompertz ancillary γ-parameter closely related to the Cox time-varying covariate, implying that the dichotomized HTI score violated the PH assumption, though this was not a prerequisite for parametric analysis. Consequently, the impact of the predicted HT risk on any HT was strongest initially but waned over time (Fig. 8C), whereas the treatment effect of Cerebrolysin remained constant. However, neither ancillary parameters nor time-varying covariates were required for symptomatic HT, indicating the effect of each variable did not change over time (Fig. 3). The PH assumption might have been met due to a shorter time frame for symptomatic HT occurrence (Fig. 2C, D), as the influence of predicted HT risk had not yet declined.

In patients with HTI > 0, the benefits of Cerebrolysin were even more pronounced with parametric analysis (Fig. 5–7, Table 4). On average, Cerebrolysin treatment delayed HT by nearly 2 days over a fortnight (Fig. 2E, F, 5). The ARR stabilized at approximately 15% after an initial increase over 3 days (Fig. 6), while the NNT plateaued at around 7 (Fig. 7). The population attributable fraction suggested that treating all HT-prone patients with Cerebrolysin might have reduced symptomatic and any HT rates to 57.3% and 71.6%, respectively (Table 4). In contrast, the intervention was ineffective in patients with HTI = 0.

Table 4

Parametric survival analysis: Time-related effects of Cerebrolysin treatment adjusted for the dichotomized HTI score.
	Symptomatic HT	Any HT
HR (95% CI, p-value)	0.245 (0.072–0.837, 0.025)	0.543 (0.297–0.991, 0.047)
Romano–Wolf p-value	0.020	0.032
Population attributable fraction (95% CI, p-value)
All patients	0.466 (0.239–0.626, 0.001)	0.282 (0.052–0.457, 0.019)
HTI > 0	0.427 (0.184–0.598, 0.002)	0.284 (0.063–0.452, 0.015)
Difference in RMST (95% CI, p-value), d
HTI = 0	0.258 (-0.120–0.635, 0.181)	0.380 (-0.045–0.806, 0.080)
HTI > 0	1.795 (0.501–3.088, 0.007)	1.998 (0.141–3.855, 0.035)
ARR (95% CI, p-value)
HTI = 0	0.020 (-0.009–0.049, 0.181)	0.036 (-0.003–0.076, 0.074)
HTI > 0	0.138 (0.039–0.238, 0.007)	0.156 (0.011–0.301, 0.035)
NNT (95% CI, p-value)
HTI = 0	50.191 (-23.341–123.723, 0.181)	27.536 (-2.625–57.698, 0.074)
HTI > 0	7.238 (2.023–12.454, 0.007)	6.423 (0.445–12.401, 0.035)
Note: The ARR, NNT, and RMST differences were calculated at the 14-day time horizon.

Figure 5.

Figure 6.

Figure 7.

Table 4.

In patients with HTI = 0, the inception points for the timing of restarting anticoagulation commenced at the two-day horizon, regardless of assigned treatment and HT type (Fig. 8A, B, Table 5). Conversely, inception varied in patients with HTI > 0 depending on allocated status and HT type. On average, Cerebrolysin treatment shortened the hazardous period by 1–2 days (Fig. 8A-C). According to the Gompertz model for symptomatic HT, the Cerebrolysin HD curves dropped below the threshold on days 2–3, whereas the control lines intersected it on days 4–5 (Fig. 8A). Similarly, the Cox TD model for any HT indicated the hazardous period ended on days 2–4 in the Cerebrolysin arm, while inception points under standard care were reached on days 3–5 (Fig. 8C). The Gompertz model for any HT provided more conservative estimates: days 4–5 and 5–6 for the Cerebrolysin and control groups, respectively (Fig. 8B). This delay might be attributed to asymptomatic HT, which could have been more accurately accounted for with an interval-censored approach.

Table 5

Inception points for resuming anticoagulation therapy.
	Symptomatic HT, Gompertz model	Any HT, Gompertz model		Any HT, Cox TD model
HD threshold	0.002	0.004	Reference line	1
Control (95% CI)			HR, crude (95% CI)
HTI = 0	2.606 (1.115–4.326)	1 (< 1–3.791)
HTI > 0	4.824 (3.791–7.003)	5.971 (5.015–7.5)	HTI > 0	4.824 (2.453– > 14)
Cerebrolysin (95% CI)			HR, adjusted for Cerebrolysin (95% CI)
HTI = 0	1.115 (< 1–2.950)	< 1 (< 1–2.874)
HTI > 0	3.294 (2.147–5.015)	5.053 (4.212–6.315)	HTI > 0	3.294 (1.574 – > 14)

Figure 8.

Table 5.

The Hausman specification test revealed that the Gompertz model for symptomatic HT was consistent, while the Cox TD model for any HT was efficient (χ²(2) = 2.39, p = 0.302), suggesting that the coefficients were not significantly different. Similarly, the test indicated no substantial difference between the Cox TD model for any HT and the Gompertz model for any HT (χ²(2) = 1.23, p = 0.540). Both Gompertz models for symptomatic HT and any HT were also consistent and efficient (χ²(2) = 5.18, p = 0.075). Therefore, due to the lack of significant differences, the Gompertz model for symptomatic HT was selected for further inference, given its consistency, efficiency, and the serious nature of symptomatic HT as a stroke complication. Based on this model, anticoagulation therapy could be safely restarted on days 2–3 with Cerebrolysin treatment and on days 4–5 with standard care in patients with HTI > 0. For patients with HTI = 0, anticoagulation therapy could be resumed safely the following day, regardless of the treatment.

This study successfully evaluated the timing of anticoagulation resumption and Cerebrolysin’s effectiveness in reducing HT risk in MCA stroke patients, providing clinically relevant insights. By conducting a post hoc survival analysis of the CEREHETIS trial, which focused on patients stratified by HTI scores, the research met its key goals. While various statistical models were used, including the Gompertz model as a supplementary tool, the main focus remains on the clinical implications of our hazard-based approach to anticoagulation timing, which directly impacts patient outcomes.

Cerebrolysin’s effect on the HT hazard varied among MCA stroke patients based on their estimated HT risk at the time of admission. Patients with a high HT risk (HTI > 0) gained substantial benefits from early treatment, while those with a low HT risk (HTI = 0) experienced only minor improvements. This variation in treatment outcomes aligns well with previous research that identifies heterogeneity in Cerebrolysin treatment effects [8, 9]. Moreover, these differences highlight the importance of tailoring clinical decisions regarding anticoagulation timing to individual patient profiles, particularly for optimizing stroke prevention.

Anticoagulation therapy with NOACs has become a cornerstone of stroke prevention in patients with non-valvular AF. However, the timing of restarting anticoagulation after a stroke remains a point of ongoing scientific debate. Although current clinical guidelines offer an empirical approach known as the 1-3-6-12-day rule [18], a growing number of randomized trials and observational studies advocate for an earlier start (within 48 h for minor-to-moderate strokes and within 4–5 days for larger strokes), which appears to be safe and could reduce the risk of early ischemic recurrence [32–34]. The proposed hazard-based time frame is consistent with these findings due to a direct correlation between predicted HT risk and stroke severity. Accordingly, patients with HTI = 0 fall into a category of minor-to-moderate stroke, while subjects with HTI > 0 suffer mostly from major stroke. Likewise, the results were coherent with our earlier study [26].

In patients with acute stroke and AF, the risk of early ischemic recurrence ranges from 0.1–1.3% per day [35] and is even higher in those with a history of anticoagulation [36, 37]. While anticoagulation therapy is essential for preventing further ischemic events, early studies indicated that using heparin within 48 h increased the risk of hemorrhagic complications. More recent clinical trials and pooled analyses, however, suggest that initiating NOACs within 48 h does not elevate the risk of HT [16, 34, 38, 39]. Furthermore, a growing body of observational studies and meta-analyses indicates that thrombolyzed patients on NOACs do not face a substantial risk of bleeding events [40–42]. Nevertheless, our study design excluded patients who had taken NOACs within 48 h before the index stroke, in line with both past and present clinical guidelines [43].

This evidence supports our hazard-based approach, reinforcing its relevance to NOACs and highlighting the importance of resuming anticoagulation therapy as early as possible, particularly in patients with prior anticoagulant use. In this context, Cerebrolysin may be beneficial by facilitating a quicker restart of anticoagulation, potentially improving outcomes for these high-risk individuals. Although most participants in our study did not have AF, the results remain robust because AF is incorporated into the HTI score [22], ensuring that patients with the same score have a similar probability of HT, regardless of AF status.

Building on the importance of early anticoagulation, our findings suggest that Cerebrolysin may enable earlier resumption of NOACs in high-risk patients. The benefit likely arises from Cerebrolysin’s impact on HT pathophysiology. Focal ischemia followed by reperfusion injury initiates pathological events such as excitotoxicity, blood-brain barrier disruption, and neuroinflammation, which are worsened by alteplase and contribute significantly to HT development [44–47]. Evidence from clinical and experimental studies indicates that Cerebrolysin stabilizes the blood-brain barrier, supports neurovascular unit survival, and reduces inflammation in the affected areas [6, 11, 12, 48, 49]. By addressing these underlying processes, Cerebrolysin may slow the progression of HT and reduce its overall risk.

Several adjuvant agents alongside IVT have also been studied in stroke patients [50, 51]. However, phase III clinical trials are required to confirm the observed positive results [3]. The ESCAPE-NA1 trial, a large-scale phase III study of the cytoprotective agent nerinetide, failed to demonstrate improvement in functional outcomes, possibly due to drug-drug interactions with alteplase. Moreover, the treatment had no effect on the HT rate in both groups [52]. In this regard, Cerebrolysin could be an alternative to nerinetide and other candidates given its ability to mitigate alteplase-related adverse effects [12], well-established safety profile, and long-lasting clinical use worldwide [53].

Both the ‘standard’ 1-3-6-12-day principle [18] and the recently proposed 1-2-3-4-day rule [39], rely solely on stroke severity, as assessed by the NIHSS, to determine the timing of restarting anticoagulation therapy. While straightforward, this approach could underestimate the complexity of HT, hence using composite scores for HT prediction appears to be more rational. Several tools have been proposed, and although many are reliable and comprised of similar predictors, only the HTI score takes into account the vascular territory of the infarcted brain lesions. Our earlier studies have suggested that the predictive ability of the HTI score is much better than other tools [8, 9, 22, 26]. Given numerous well-established differences between stroke in the anterior and posterior circulation, this could explain why the HTI score outperforms others in patients with MCA infarction.

Since a seminal paper on IVT-related symptomatic HT was published in 1997 [54], investigators have looked at the follow-up period as a whole rather than as a continuum of instantaneous moments, reporting results by means of the HT odds ratio and descriptive statistics. To our knowledge, few authors have attempted to apply nonparametric and semiparametric survival analysis on this topic [39, 55]. However, we have used far more advanced methods to assess the HT time frame in stroke patients, and the implications of our work could serve as theoretical grounds for future research.

The emergence of next-generation intravenous thrombolytics and advancements in endovascular thrombectomy present new challenges for HT risk assessment and necessitate further refinement of HT preventive strategies and the timing of restarting anticoagulation therapy [32, 50]. In this respect, the results of an ongoing clinical trial on the efficacy of Cerebrolysin as adjuvant therapy to endovascular thrombectomy in anterior circulation stroke due to large vessel occlusion will be very promising [56].

Future research should validate Cerebrolysin’s efficacy across a range of stroke severities and patient populations to enhance generalizability. Studies could focus on its effects in patients with comorbidities that may influence outcomes. Conducting prospective, real-world trials will be crucial for confirming these findings in clinical settings. Research could explore the combination of Cerebrolysin with next-generation thrombolytics like tenecteplase and advanced endovascular thrombectomy techniques such as aspiration thrombectomy or stent retrievers. Additionally, examining Cerebrolysin’s role in patients on dual antiplatelet therapy or NOACs will provide insights into its effectiveness and safety in diverse therapeutic contexts. Assessing the long-term benefits and safety of Cerebrolysin in combination with these advanced reperfusion strategies is essential for refining treatment guidelines and improving acute stroke care outcomes.

The study’s major strength lies in its detailed HT risk stratification of stroke patients. By identifying and categorizing patients based on their HT risk, the study provides tailored insights into the efficacy of Cerebrolysin treatment, allowing for more personalized medical interventions. The research demonstrates methodological rigor through the use of a comprehensive blend of nonparametric, semiparametric, and parametric approaches in survival analysis, which enhances the reliability of the findings and ensures that multiple aspects of the data are thoroughly examined. The study’s results have significant clinical implications, particularly regarding the timing of restarting anticoagulation therapy based on HT risk. These findings align with recent clinical trials and observational studies, reinforcing their validity and providing a foundation for future clinical guidelines, suggesting that the study’s conclusions are robust and reliable. Additionally, the study demonstrates that Cerebrolysin can reduce the hazard of HT and shorten the time required to safely restart anticoagulation therapy, particularly in high-risk patients, highlighting its potential benefits as an adjunctive treatment in stroke management.

Despite the study’s strengths, several key limitations warrant attention. The conclusions regarding the timing of restarting anticoagulation therapy are based on hazard function analyses rather than real-world clinical trials, which may reduce the external validity of these findings in clinical practice. Additionally, the study’s focus on patients with MCA strokes limits the generalizability of the results to other stroke types, such as those affecting the posterior circulation. The exclusion of patients with HTI scores greater than 4 further restricts our understanding of Cerebrolysin’s effects on individuals at the highest HT risk. While the study provides robust evidence, the relatively small sample size in certain subgroups may reduce statistical power, necessitating cautious interpretation. Furthermore, as a post hoc analysis, the research faces inherent challenges, including the risk of identifying statistically significant results that might not reflect true relationships, potentially introducing bias and affecting the overall validity of the conclusions.

This study demonstrates that Cerebrolysin may reduce the risk of HT and enable earlier, safer resumption of anticoagulation in stroke patients at high HT risk. These findings highlight the potential of Cerebrolysin as an adjunctive therapy in risk-based stroke management. While the study provides valuable insights, its results are tempered by certain methodological and generalizability factors. Further research is needed to validate these findings in broader clinical settings and explore additional combinations with advanced reperfusion strategies to strengthen the evidence base for Cerebrolysin in stroke management.

AF, atrial fibrillation;

ARR, absolute risk reduction;

ASPECTS, Alberta Stroke Program Early Computed Tomography Score;

CI, confidence interval;

HD, hazard deceleration;

HR, hazard ratio;

HT, hemorrhagic transformation;

HTI, Hemorrhagic Transformation Index;

IQR, interquartile range;

IVT, intravenous thrombolysis;

M, median

MCA, middle cerebral artery;

NIHSS, National Institutes of Health Stroke Scale;

NNT, number needed to treat;

NOAC, non-vitamin K antagonist oral anticoagulant;

PH, proportional hazard;

RMST, restricted mean survival time;

TD, time-dependent

Conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval

The original trial received approval from the Local Ethics Committee of the Interregional Clinical Diagnostic Center in Kazan, Russia (Protocol #81, dated April 24, 2018), and all participants or their legal representatives provided written informed consent. The current study, a post hoc analysis of the original research, did not require separate ethical approval. All study procedures were conducted in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Contributorship

MNK: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. DRK: Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – review & editing. All authors have read and approved the manuscript.

Acknowledgements

Not applicable.

Data availability

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

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Cerebrolysin, Hemorrhagic Transformation, and Anticoagulation Timing after Reperfusion Therapy in Stroke: Secondary Analysis of the CEREHETIS Trial

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