What is the role of citicoline (cytidine diphosphate-choline) in the treatment of stroke patients?

Citicoline in Stroke Patients: Current Evidence and Recommendations

Citicoline is not recommended for the treatment of patients with acute ischemic stroke as multiple clinical trials have failed to demonstrate consistent efficacy in improving outcomes. 1

Evidence Assessment

• The American Heart Association/American Stroke Association guidelines explicitly state that no agent with putative neuroprotective effects, including citicoline, can be recommended for the treatment of patients with acute ischemic stroke (Grade A recommendation) 2

• Despite citicoline's theoretical neuroprotective mechanisms (stabilizing cell membranes and reducing free radical generation), clinical trials have not demonstrated consistent benefits:

  • Initial trials showed mixed results with some post-hoc analyses suggesting potential benefit 3, 4
  • A pooled analysis suggested possible benefit in reducing disability when started within 24 hours, but this finding was not supported by subsequent definitive trials 1
  • The International Citicoline Trial on Acute Stroke (ICTUS), a large multicenter randomized trial with 2,298 patients, found no difference in 90-day global outcomes between citicoline and placebo 1

• A specific concern noted in guidelines is that none of the individual clinical trials was able to find a consistent benefit from treatment with citicoline, even though a post-hoc analysis found recovery at 3 months in 25.2% of citicoline-treated patients versus 20.2% of placebo-treated patients 2

Safety Profile

• Citicoline appears to have a favorable safety profile with minimal side effects reported across studies:
  • In a large surveillance study of 4,191 patients, only 0.73% experienced side effects, most commonly nervous system-related symptoms (21.62%) and gastrointestinal symptoms (13.5%) 5
  • The incidence and types of side effects were similar between citicoline and placebo groups in controlled trials 3, 4

Potential Subgroups and Dosing

• Some post-hoc analyses have suggested potential benefit in specific subgroups:

  • Patients with moderate to severe strokes (NIHSS ≥8) might show better recovery rates with citicoline treatment 4
  • Higher doses (≥2000 mg/day) appeared to show more significant improvements in some observational studies 5
  • Early administration (within 24 hours of stroke onset) might be more effective than delayed treatment 5

• However, these subgroup findings from post-hoc analyses should be interpreted with caution as they were not confirmed in subsequent trials designed to test these hypotheses 1

Current Approach to Stroke Management

• For acute ischemic stroke management, focus should remain on established evidence-based interventions:
  • Rapid evaluation for thrombolysis with rtPA within the appropriate time window 1
  • Early initiation of antiplatelet therapy (aspirin) within 24-48 hours of stroke onset in non-thrombolyzed patients 1
  • Management of physiological parameters, including blood pressure control 1
  • Admission to a stroke unit for specialized care and monitoring 2

Conclusion

Despite theoretical benefits and some promising preclinical data 6, citicoline cannot be recommended for routine use in acute ischemic stroke patients based on the current highest quality evidence. The focus should remain on established evidence-based interventions that have demonstrated efficacy in improving stroke outcomes.