Summary of findings 1. Cerebrolysin compared to placebo for acute ischaemic stroke.

Cerebrolysin compared to placebo for acute ischaemic stroke
Patient or population: people with acute ischaemic stroke Settings: inpatient health facilities in 7 European countries: Austria, Croatia, the Czech Republic, Hungary, Russia, Slovakia, Slovenia; and 5 Asian countries: China, Hong Kong, Iran, Myanmar, South Korea Intervention: Cerebrolysin added to standard therapy (in most studies aspirin; in 1 study thrombolysis) Comparison: placebo added to standard therapy (in most studies aspirin; in 1 study thrombolysis)
Outcomes		Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
		Assumed risk	Corresponding risk
		Placebo	Cerebrolysin
All‐cause death at the end of the follow‐up period		65 per 1000	59 per 1000 (40 to 86)	RR 0.89 (0.60 to 1.31)	1517 (6 RCTs)	⊕⊕⊕⊝ Moderatea,b,c,d
Total number of people with SAEs	at the end of the follow‐up period	72 per 1000	83 per 1000 (59 to 119)	RR 1.15 (0.81 to 1.65)	1435 (4 RCTs)	⊕⊕⊕⊝ Moderatea,b,c,d
	fatal, at the end of the follow‐up period	63 per 1000	57 per 1000 (37 to 87)	RR 0.90 (0.59 to 1.38)	1335 (3 RCTs)	⊕⊕⊕⊝ Moderatea,b,c,d
	non‐fatal, at the end of the follow‐up period	14 per 1000	30 per 1000 (14 to 63)	RR 2.15 (1.01 to 4.55)	1435 (4 RCTs)	⊕⊕⊕⊝ Moderatea,b,c,d
	non‐fatal: a subgroup by Cerebrolysindose and length of treatment, at the end of the follow‐up period	12 per 1000	33 per 1000 (14 to 78)	RR 2.86 (1.23 to 6.66)	1189 (2 RCTs)	⊕⊕⊕⊝ Moderateg,h,i,j
Total number of people with adverse events at the end of the follow‐up period		447 per 1000	452 per 1000 (402 to 501)	RR 1.01 (0.9 to 1.12)	1435 (4 RCTs)	⊕⊕⊝⊝ Lowa,c,d,e
Non‐death attrition		155 per 1000	151 per 1000 (70 to 320)	RR 0.97 (0.45 to 2.06)	1517 (6 RCTs)	⊕⊝⊝⊝ Very lowa,d,f
Death or dependence at the end of the follow‐up period		Not reported	Not reported	‐	1601 (7 RCTs)	‐
Early death (within 2 weeks of stroke onset)		Not reported	Not reported	‐	1601 (7 RCTs)	‐
Quality of life		Not reported	Not reported	‐	1601 (7 RCTs)	‐
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial: RR: risk ratio; SAE: serious adverse event
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

^aWe downgraded by one level for risk of bias because most information came from studies at low or unclear risk of bias.
^bNo serious inconsistency. Six trials contributed to the outcome all‐cause death; we did not detect any heterogeneity. Three eligible multicentre studies contributed to the outcomes total number of people with SAEs, total number of people with fatal SAEs, and total number of people with non‐fatal SAEs, and the newly included Gharagozli 2017 study contributed to the outcomes total number of people with SAEs and total number of people with non‐fatal SAEs. We detected no statistical heterogeneity for any of these outcomes.
^cNo serious imprecision: the six trials that contributed to the primary outcome all‐cause death, synthesised with a total of 1517 participants, had enough power to detect difference. There was no significant difference: 47 deaths in Cerebrolysin group (out of 764 randomised participants) and 49 deaths in placebo group (out of 753 randomised participants). Although the confidence intervals were wide, there was no heterogeneity; the four studies that contributed to the outcomes total number of people with SAEs, total number of people with non‐fatal SAEs, and total number of people with adverse events, of which three were multicentre, synthesised totalling 1435 participants, would have had enough power to detect differences.
^dNo serious indirectness. The studies, three of which were multicentre, were conducted in seven European countries: Austria, Croatia, the Czech Republic, Hungary, Russia, Slovakia, Slovenia; and five Asian countries: China, Hong Kong, Iran, Myanmar, South Korea. The results can be generalised to other populations and situations between 2003 and 2014.
^eWe downgraded by one level for inconsistency. Four trials contributed to the outcome total number of people with adverse events; we detected heterogeneity with I² = 37% for the overall effect estimate owing to the opposite direction of effect estimate in the Ladurner 2005 study, which used the high cumulative dose of Cerebrolysin, and heterogeneity with I² = 65% in the subgroup of two multicentre studies with the same dosing schedule (CASTA 2012; CERE‐LYSE‐1 2012).
^fWe downgraded once for inconsistency and once for imprecision. Six trials contributed to the outcome non‐death attrition; we detected heterogeneity with I² = 76% for the overall effect estimate and I² = 81% for subgroup differences owing to the opposite direction of effect estimate in the Ladurner 2005 study (the high cumulative dose of Cerebrolysin) and the Gharagozli 2017 study (the low cumulative dose of Cerebrolysin), and heterogeneity with I² = 47% in the subgroup of two multicentre studies with the same dosing schedule (CASTA 2012; CERE‐LYSE‐1 2012). The confidence intervals were wide.

^gDowngraded by one level for risk of bias. These two newer multicentre studies, which contributed to the outcome total number of people with non‐fatal SAEs, were considered across domains of unclear and high risk of bias due to high levels of exclusions from the final analyses, retrospective registration, and multiple other methodological flaws as described in Assessment of risk of bias in included studies. The manufacturer of Cerebrolysin supported CASTA 2012 and CERE‐LYSE‐1 2012 by providing services including: provision of Cerebrolysin and placebo, randomisation codes, statisticians, funding of study authors.
^hNo serious inconsistency. The two multicentre studies contributed to the outcome total number of people with non‐fatal SAEs. We detected no statistical heterogeneity.
ⁱNo serious imprecision. The two multicentre studies, when synthesised totalling 1189 participants, had enough power to detect the difference: 20 SAEs in the Cerebrolysin group (589 randomised participants) and seven SAEs in the placebo group (600 randomised participants); there was no heterogeneity.
^jNo serious indirectness. These two studies were conducted in five European countries: Austria, Croatia, the Czech Republic, Slovakia, Slovenia; and in four Asian countries: China, Hong Kong, South Korea, Myanmar. The results can be generalised to other populations and situations.