Uric Acid Therapy Prevents Early Ischemic Stroke Progression

Abstract

Background and Purpose— Identification of neuroprotective therapies in acute ischemic stroke is imperative. We report a predefined analysis of the URICO-ICTUS trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke) assessing the efficacy of uric acid (UA) compared with placebo to prevent early ischemic worsening (EIW) and the relevance of collateral circulation. Methods— URICO-ICTUS was a double-blind, placebo-controlled, phase 2b trial where a total of 411 patients treated with alteplase within 4.5 hours of stroke onset were randomized (1:1) to receive UA 1000 mg (n=211) or placebo (n=200) before the end of alteplase infusion. EIW defined an increment ≥4 points in the National Institutes of Health Stroke Scale score within 72 hours of treatment in the absence of hemorrhage or recurrent stroke. Logistic regression models assessed the interaction between therapy and the collateral circulation in 112 patients who had a pretreatment computed tomographic angiography. Results— EIW occurred in 2 of 149 (1%) patients with good outcome and 23 of 262 (9%) patients with poor outcome (χ 2 ; P =0.002). EIW occurred in 7 of 204 (3%) patients treated with UA and in 18 of 200 (9%) patients treated with placebo (χ 2 ; P =0.01). There was a significant interaction between the efficacy of UA to prevent EIW and collaterals ( P =0.029), with lower incidence in patients with good collaterals treated with UA compared with placebo (2% versus 15%, respectively; P =0.048). Conclusions— UA therapy may prevent EIW after acute stroke in thrombolysed patients. Optimal access of UA to its molecular targets through appropriate collaterals may modify the magnitude of the neuroprotective effect. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00860366.

Uric acid enhances alteplase-mediated thrombolysis as an antioxidant

“…This suggests that UA suppresses the inhibitory action of oxidative stress on alteplase-mediated thrombolysis (Fig. 7 ) in agreement with previous clinical studies 5 .

Figure 7 Schema showing the potential actions of UA against oxidative stress in thrombolytic pathways.

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“…To clarify the mechanism of the synergistic effects of UA in the URICO-ICTUS trial 5 , we evaluated whether UA enhances alteplase-mediated thrombolysis under flow conditions using the T-TAS in human whole blood. After perfusion had started, plentiful small white thrombi were observed adhering to the coated surface.…”

“…The URICO-ICTUS trial (Efficacy Study of Combined Treatment with Uric Acid and rtPA in Acute Ischemic Stroke) showed that uric acid (UA) therapy significantly reduced the incidence of early ischemic worsening compared with placebo in patients treated with alteplase within 4.5 hours of AIS onset 5 . In experimental stroke models, UA therapy reduced brain damage and acted synergistically with alteplase in thromboembolic models 6 .…”

U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke

“…We cannot confirm the role of UA treatments on the stroke outcomes. URICO-ICTUS trial suggested that UA therapy may prevent early ischemic worsening (EIW) after acute stroke in thrombolysed patients [36]. In women with acute ischemic stroke treated with alteplase, the administration of UA reduced infarct growth in selected patients and was better than placebo to reach excellent outcome [26].…”

Reconsidering Neuroprotection in the Reperfusion Era

“…Another promising treatment that may target oxidative injury in ischemic stroke exacerbated by hyperglycemia is uric acid. Post hoc studies of the URICOICTUS trial have shown possible benefits of uric acid in those patients with early reperfusion, 36 good collaterals, 37 or pretreatment hyperglycemia. 36 Because there are now proven effective treatments for reperfusion, the possibility of pursuing dedicated clinical studies of adjunctive treatments targeting oxidative stress and inflammation along with pharmacological thrombolysis and mechanical thrombectomy exists.…”