URICO-ICTUS: Uric Acid Beneficial for Stroke?

February 12, 2014

SAN DIEGO, California — Giving stroke patients uric acid along with standard thrombolysis within 4.5 hours of first symptoms may reduce disability, according to the results of the URICO-ICTUS study.

The proof-of-concept study was presented today at the American Stroke Association (ASA) International Stroke Conference (ISC) 2014 by Angel Chamorro, MD, Comprehensive Stroke Center, Hospital Clinic, Barcelona, Spain.

"While we did not show a significant benefit in the primary outcome, there was an encouraging trend and there were benefits in several secondary outcomes," Dr. Chamorro concluded. "We have to interpret these results cautiously, but I think they are enough to warrant performing a larger, more definitive trial." However, he added, "The results of this trial are exciting and offer new hope in a field that was full of failures."

Moderator of the ASA press conference on the study, Steven Greenberg, MD, professor of neurology at Harvard Medical School, Boston, Massachusetts, commented to Medscape Medical News. "While we should leave the corks in the champagne bottles until definitive trials have been conducted, I do think these results are intriguing."

Noting that uric acid acts as a free radical scavenger, mopping up the free radicals generated by lack of blood flow during stroke that are believed to cause brain cell death, Dr. Greenberg said, "Similar approaches with other neuroprotectants have not panned out, but we are optimistic that with the right treatment at the right time, success is possible."

For this phase 2b/3 study, 421 stroke patients treated with alteplase within 4.5 hours of symptom onset were randomly assigned to a 1-g infusion of uric acid or to placebo.

The primary endpoint of the trial was the proportion of patients with an "excellent outcome" at 90 days, defined as a modified Rankin scale (mRS) score of 0 to 1, or an mRS score of 2 in patients who had a score of 2 before stroke onset. This showed a nonsignificant improvement with uric acid.

Table 1. URICO-ICTUS: Primary Outcome

Endpoint Placebo (n = 200) Uric Acid (n = 211) RR (95% CI) P Value
mRS score, 0-1 (or 2 if score was 2 before stroke), n (%) 66 (33) 83 (39.3) 1.23 (0.96 - 1.56) .099

CI, confidence interval; RR = relative risk.

 

In addition, a shift analysis using the mRS showed a significant reduction in poor outcome in the uric acid group.

Table 2. URICO-ICTUS: Shift Analysis

Endpoint Placebo Uric Acid P Value
Median mRS score (interquartile range) 3 (1 - 4) 2 (1 - 4) .045

 

Table 3. URICO-ICTUS: Other Secondary Outcomes

Endpoint Placebo (%) Uric Acid (%) RR (95% CI) P Value
NIHSS ≤1 at 2 h 6.5 5.7 0.86 (0.40 - 1.82) .686
NIHSS ≤1 at 90 d 30.5 34.1 1.14 (0.88 - 1.50) .325
Barthel index score > 94 at 90 d 40.5 48.3 1.22 (0.99 - 1.49) .057
Worsening at 3 d 9.0 3.3 .025

NIHSS = National Institutes of Health Stroke Scale. Worsening defined as increment of at least 4 points on the NIHSS score.

 

The greatest benefits of uric acid were seen in women, patients with a moderate-large stroke, and patients with high blood glucose. Dr. Chamorro suggested this may because these patients have a higher oxidative burden. "But we have to be cautious as this is just an exploratory analysis," he added.

 
When used in stroke, uric acid is a fire-fighter, not an arsonist. Dr. Angel Chamorro
 

He pointed out that some may be surprised at the idea of using uric acid in stroke because high levels can lead to kidney stones and gout and have been linked with heart and vascular problems and diabetes. "But what people do not know so well is that uric acid is an extremely potent antioxidant. When used in stroke, uric acid is a fire-fighter, not an arsonist," he added. Indeed, the incidence of gout was actually reduced in the uric acid group at 90 days: 0.5% vs 2.0% with placebo (P = .194).

"Although the main outcome was neutral, we set an ambitious target of a 14% absolute difference between the groups in terms of the primary outcome. This was the difference needed to show significance with just 450 patients in the study, which is all we had funds for. But we did show a 6% difference and some promising effects on secondary outcomes. We are hoping this will be enough to obtain funds for a larger study," Dr. Chamorro said. He has now applied for a grant for a further 1500-patient study.

Asked whether uric acid would need to be given with tissue plasminogen activator (tPA) or whether it may still be effective without thrombolysis, Dr. Chamorro replied, "We haven't the evidence to know this, but in this study the response appeared to be maintained in patients in whom the artery was not opened. So it is possible that it may work without tPA. But this is something I say very cautiously."

He added that uric acid also had potential as a neuroprotectant in other conditions, such as Parkinson's disease and head trauma.

International Stroke Conference (ISC) 2014. Abstract LB1. Presented February 12, 2014.

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