In an adult acute ischemic stroke patient receiving tissue plasminogen activator or endovascular therapy, which adjunct neuroprotective agent—edaravone (intravenous) or citicoline (oral)—is preferred considering safety and efficacy?

Edaravone vs Citicoline for Acute Ischemic Stroke

Neither edaravone nor citicoline should be used as adjunct neuroprotective agents in acute ischemic stroke patients receiving thrombolysis or endovascular therapy, as current American Heart Association/American Stroke Association guidelines explicitly state that no pharmacological neuroprotective agents have demonstrated efficacy in improving outcomes and therefore cannot be recommended (Class III: No Benefit, Level of Evidence A). 1, 2, 3, 4

Guideline-Based Recommendations

Citicoline: Not Recommended

• The AHA/ASA issues a Grade A (strong) recommendation against citicoline use in acute ischemic stroke based on definitive negative trial data. 3
• The International Citicoline Trial on Acute Stroke (ICTUS) enrolled 2,298 patients with moderate-to-severe ischemic stroke and found no difference in 90-day functional outcomes (OR 1.03,95% CI 0.86-1.25, p=0.364), leading to premature trial termination for futility. 1, 2, 3, 4
• Multiple earlier trials similarly failed to demonstrate treatment efficacy, and a systematic review confirmed no consistent benefit. 1, 2
• While a patient-level pooled analysis suggested potential benefit when started within 24 hours, this finding was contradicted by the subsequent definitive ICTUS trial. 1, 2

Edaravone: Insufficient Evidence for Recommendation

• Edaravone has not been adequately studied in large, high-quality trials to support its use in acute ischemic stroke. 1
• A small clinical trial suggested edaravone might improve outcomes, but the AHA/ASA guidelines state that "to date, none of these agents have sufficient data to support their use." 1
• The 2018 AHA/ASA guidelines explicitly state that no neuroprotective agents, including free radical scavengers like edaravone, can be recommended. 1

Evidence Quality Comparison

Why Guidelines Reject Both Agents

Citicoline has stronger evidence—but it's negative evidence. The ICTUS trial represents the highest quality data available: a large, multicenter, randomized, placebo-controlled trial that definitively showed no benefit. 1, 2, 3

Edaravone lacks high-quality evidence entirely. Only small pilot studies exist, which is insufficient to overcome the consistent failure of neuroprotective agents in stroke trials. 1

Research Data Context (Not Practice-Changing)

While recent meta-analyses suggest edaravone may improve functional outcomes (OR=1.31 for good outcomes at 90 days) and reduce mortality (OR=0.50), these findings come predominantly from observational studies in Asian populations, particularly Japan, with high heterogeneity. 5, 6 A 2024 network meta-analysis ranked edaravone among the safest and most effective neuroprotective agents, but this contradicts guideline-level evidence and lacks the rigor of definitive RCTs. 6

A single 2012 head-to-head comparison (n=66) found edaravone superior to citicoline in moderate-to-severe stroke (mean NIHSS 4.46 vs 10.28, p=0.00), but this small study cannot override guideline recommendations. 7

What to Do Instead

Focus on proven reperfusion and supportive therapies:

• Intravenous alteplase within 3-4.5 hours of symptom onset for eligible patients (Class I, Level A). 3, 4
• Endovascular thrombectomy for large vessel occlusions within guideline-specified time windows (Class I, Level A). 3, 4
• Aspirin 160-325 mg within 24-48 hours after excluding hemorrhage in patients not receiving thrombolysis (Class I, Level A). 1, 3, 4
• Blood pressure management: Maintain <185/110 mmHg before and <180/105 mmHg for 24 hours after thrombolysis. 1, 4

Critical Pitfalls to Avoid

• Do not delay proven therapies (thrombolysis, thrombectomy, aspirin) to administer unproven neuroprotective agents. 1, 2
• Do not use citicoline based on older meta-analyses—the definitive ICTUS trial supersedes these findings. 1, 2, 3
• Do not extrapolate edaravone data from Japanese practice to other populations without high-quality RCT evidence. 5
• Recognize that "neuroprotection" has failed repeatedly in stroke trials despite promising preclinical data—over 1,000 agents tested, none proven effective. 1