G-CSF Fails to Benefit Acute Ischemic Stroke Patients

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Despite showing preclinical promise, granulocyte colony-stimulating factor (G-CSF) fails to improve clinical outcomes in acute ischemic stroke patients, according to results published online August 20, 2013, ahead of print in Stroke.

Researchers led by E. Bernd Ringelstein, MD, of University of Münster (Münster, Germany), randomized 324 patients with acute ischemic stroke presenting within 9 hours of symptom onset to G-CSF (n = 161; cumulative dose of 135 µg/kg body weight given as IV bolus plus continuous IV infusion over 72 hours) or placebo (n = 163).

A total of 65 patients died over 90-day follow-up, including 35 (21.7%) in the G-CSF group and 30 (18.4%) in the placebo group (P = 0.4). The most common causes of death were bronchopneumonia, cerebrovascular accident, and brain edema. All serious adverse events leading to death were judged not related or unlikely to be related to study medication with the exception of 1 brain edema in the G-CSF group attributed to the medication.

Primary, Secondary Endpoints Similar

At 90 days, there were no differences in the modified Rankin Scale score (primary endpoint) or in the National Institutes of Health Stroke Scale (NIHSS) score or infarct volume between the 2 groups by intention-to-treat analysis (table 1).

Table 1. Mean Outcomes at 90 Days




P Value

Modified Rankin Scale Score








Infarct Volume, cm3




The results, including mortality, were likewise similar between groups on per-protocol analysis.

No Difference by Previous Thrombolysis

Patients who received recombinant tissue plasminogen activator (rt-PA) had better modified Rankin Scale scores than those not treated with rt-PA, but there was no difference between these subgroups with regard to the efficacy of G-CSF (P = 0.29 for G-CSF vs. placebo in patients not given rt-PA; P = 0.92 for G-CSF vs. placebo in those given rt-PA).

Likewise, no significant differences in NIHSS score at 90 days with regard to G-CSF treatment could be detected in the rt-PA-treated and untreated subgroups.

While final infarct volume did not differ between treatment groups, there was an initial disadvantage for G-CSF due to a larger perfusion deficit and a larger mismatch area at baseline. Considering the smaller total and cortical final infarct volumes, it could be speculated that there was an efficacy signal on lesion growth, the authors note. An exploratory analysis of the final infarct volume taking into account perfusion weighted imaging (PWI) deficit, treatment group, and rt-PA co-treatment revealed interactions between PWI and treatment group (P < 0.01), suggesting that G-CSF may have an inhibitory effect on infarct growth in patients with large PWI deficits.

Dr. Ringelstein and colleagues also point out that G-CSF showed promise as a therapy for acute ischemic stroke in preclinical studies. In particular, the drug had improved long-term functional recovery after stroke even if treatment was delayed for days. “Unfortunately, the promising preclinical data could not be translated into clinical efficacy in a larger patient cohort,” they acknowledge.

Researchers Speculate About Dose, Timing

The question is, why was clinical efficacy elusive? “It is possible that this was not the optimal dose selected,” the researchers theorize, “and it is also possible that a longer duration of the treatment could have been beneficial. However, the total lack of treatment response makes it questionable whether a comparably small change in treatment dose or timing would have produced a therapeutically relevant effect.”

There were several unexpected effects of G-CSF on physiological parameters, they note, such as a lowering of serum potassium and a doubling of the incidence of hypokalemia. There was a decrease in mean arterial blood pressure, and increases were also noted in heart rate, mean body temperature (by 0.2°C), and reported fever.

“Despite their small effect size, several of these systemic effects may have counteracted potential beneficial effects of the drug,” the authors observe. Nevertheless, they conclude that “G-CSF does not improve stroke outcome after 90 days when applied as 3-day intravenous therapy, despite promising preclinical and clinical data. This result strengthens the notion of a principal problem in translating findings from the animal laboratory to clinical stroke patients whose basis is currently not understood.”


Ringelstein EB, Thijs V, Norrving B, et al. Granulocyte colony-stimulating factor in patients with acute ischemic stroke. Results of the AX200 for ischemic stroke trial. Stroke. 2013;Epub ahead of print.



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  • The study was funded by Sygnis Bioscience.
  • Dr. Ringelstein reports receiving fees and expenses from Sygnis for his steering board work.

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