Uric acid for stroke trials to continue

SAN DIEGO – Adding uric acid to thrombolytic therapy for acute stroke looked promising enough in a double-blind placebo-controlled trial of 420 adult patients that investigators will seek funding for a larger trial.

Thirty-nine percent of 211 patients randomized to the uric acid group achieved an "excellent" outcome on measures of symptoms and function 90 days later, but the 200 patients in the placebo group also had a robust response with 33% achieving excellent outcomes, Dr. Angel Chamorro reported at the International Stroke Conference. Nine patients were excluded from the analysis because they didn’t take the medication or were determined not to have a stroke.

The difference between groups did not reach statistical significance, and the study was not powered to assess less than a 14% difference between groups. Safety outcomes were similar between groups, however, and statistical trends toward better outcomes with uric acid in this proof-of-concept trial are enough to justify a study of 1,500 patients to determine whether this is a useful treatment, said Dr. Chamorro, director of the comprehensive stroke center at Hospital Clinic of the University of Barcelona (Spain).

If the results are validated in subsequent trials, it could mean that for every 14 patients given uric acid for acute stroke, 1 patient would become completely free of stroke symptoms, he said in an interview. Uric acid, a potent antioxidant, is thought to help in stroke by inhibiting free radicals that are created during loss of blood flow and that damage brain cells. Uric acid is being explored by other investigators as a treatment for Parkinson’s disease, he added.

All patients in the Urico-ictus Study were treated with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of acute ischemic stroke symptom onset and randomized to receive a single IV infusion of 1 g uric acid dissolved in vehicle or to a control group whose IV infusion contained the vehicle alone (500 mL containing 0.1% lithium carbonate and 5% mannitol). All patients had a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 6 but less than 25, a modified Rankin Scale (mRS) score no greater than 2 prior to the stroke, and a cranial CT showing the absence of blood in the CNS.

The primary results showed modified Rankin Scale scores of 0-1 (or 2 if premorbid was 2) at 90 days in 39% on uric acid and 33% on placebo (P = .099).

Among secondary outcomes, the median mRS was 2 in the uric acid group and 3 on placebo (P = .045), suggesting a trend toward greater effectiveness with uric acid. A 1-point absolute reduction in median mRS is similar to the effects seen in the first trials of thrombolytic therapy, Dr. Chamorro pointed out.

Patients on uric acid were significantly less likely to show worsening at day 3 compared with the placebo group (3% vs. 9%). The uric acid group showed a "high statistical trend" toward having fully independent functioning at 90 days as assessed by a score greater than 94 on the Barthel Index of Activities of Daily Living, with 48% on uric acid and 41% on placebo reaching this mark, Dr. Chamorro reported at the meeting, sponsored by the American Heart Association.

Thirteen percent on uric acid and 16% on placebo died within 90 days. Gout occurred within 90 days in 0.5% on uric acid and 2% on placebo. The proportions of patients with an intracranial hemorrhage whose NIHSS score worsened by 4 points within the first 36 hours of treatment were 4% in the uric acid group and 3% in the placebo groups. These safety outcomes did not differ significantly between groups.

Preplanned subgroup analyses showed trends toward greater effectiveness of uric acid in women, patients with high blood glucose levels, or those with moderate strokes, compared with placebo.

Oxidative stress in patients with ischemic stroke contributes to brain damage. The antioxidant properties of uric acid proved to be neuroprotective in animal studies. Dr. Chamorro and his associates reported in a previous prognostic study of 881 patients with acute ischemic stroke that each milligram per deciliter increase in serum uric acid was associated with a 12% increase in the odds of a good clinical outcome (Stroke 2002;33:1048-52). Previous animal studies suggest uric acid may help reduce stroke sequelae.

Dr. Chamorro and his coauthors reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN DIEGO – Adding uric acid to thrombolytic therapy for acute stroke looked promising enough in a double-blind placebo-controlled trial of 420 adult patients that investigators will seek funding for a larger trial.

Thirty-nine percent of 211 patients randomized to the uric acid group achieved an "excellent" outcome on measures of symptoms and function 90 days later, but the 200 patients in the placebo group also had a robust response with 33% achieving excellent outcomes, Dr. Angel Chamorro reported at the International Stroke Conference. Nine patients were excluded from the analysis because they didn’t take the medication or were determined not to have a stroke.

The difference between groups did not reach statistical significance, and the study was not powered to assess less than a 14% difference between groups. Safety outcomes were similar between groups, however, and statistical trends toward better outcomes with uric acid in this proof-of-concept trial are enough to justify a study of 1,500 patients to determine whether this is a useful treatment, said Dr. Chamorro, director of the comprehensive stroke center at Hospital Clinic of the University of Barcelona (Spain).

If the results are validated in subsequent trials, it could mean that for every 14 patients given uric acid for acute stroke, 1 patient would become completely free of stroke symptoms, he said in an interview. Uric acid, a potent antioxidant, is thought to help in stroke by inhibiting free radicals that are created during loss of blood flow and that damage brain cells. Uric acid is being explored by other investigators as a treatment for Parkinson’s disease, he added.

All patients in the Urico-ictus Study were treated with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of acute ischemic stroke symptom onset and randomized to receive a single IV infusion of 1 g uric acid dissolved in vehicle or to a control group whose IV infusion contained the vehicle alone (500 mL containing 0.1% lithium carbonate and 5% mannitol). All patients had a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 6 but less than 25, a modified Rankin Scale (mRS) score no greater than 2 prior to the stroke, and a cranial CT showing the absence of blood in the CNS.

The primary results showed modified Rankin Scale scores of 0-1 (or 2 if premorbid was 2) at 90 days in 39% on uric acid and 33% on placebo (P = .099).

Among secondary outcomes, the median mRS was 2 in the uric acid group and 3 on placebo (P = .045), suggesting a trend toward greater effectiveness with uric acid. A 1-point absolute reduction in median mRS is similar to the effects seen in the first trials of thrombolytic therapy, Dr. Chamorro pointed out.

Patients on uric acid were significantly less likely to show worsening at day 3 compared with the placebo group (3% vs. 9%). The uric acid group showed a "high statistical trend" toward having fully independent functioning at 90 days as assessed by a score greater than 94 on the Barthel Index of Activities of Daily Living, with 48% on uric acid and 41% on placebo reaching this mark, Dr. Chamorro reported at the meeting, sponsored by the American Heart Association.

Thirteen percent on uric acid and 16% on placebo died within 90 days. Gout occurred within 90 days in 0.5% on uric acid and 2% on placebo. The proportions of patients with an intracranial hemorrhage whose NIHSS score worsened by 4 points within the first 36 hours of treatment were 4% in the uric acid group and 3% in the placebo groups. These safety outcomes did not differ significantly between groups.

Preplanned subgroup analyses showed trends toward greater effectiveness of uric acid in women, patients with high blood glucose levels, or those with moderate strokes, compared with placebo.

Oxidative stress in patients with ischemic stroke contributes to brain damage. The antioxidant properties of uric acid proved to be neuroprotective in animal studies. Dr. Chamorro and his associates reported in a previous prognostic study of 881 patients with acute ischemic stroke that each milligram per deciliter increase in serum uric acid was associated with a 12% increase in the odds of a good clinical outcome (Stroke 2002;33:1048-52). Previous animal studies suggest uric acid may help reduce stroke sequelae.

Dr. Chamorro and his coauthors reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN DIEGO – Adding uric acid to thrombolytic therapy for acute stroke looked promising enough in a double-blind placebo-controlled trial of 420 adult patients that investigators will seek funding for a larger trial.

Thirty-nine percent of 211 patients randomized to the uric acid group achieved an "excellent" outcome on measures of symptoms and function 90 days later, but the 200 patients in the placebo group also had a robust response with 33% achieving excellent outcomes, Dr. Angel Chamorro reported at the International Stroke Conference. Nine patients were excluded from the analysis because they didn’t take the medication or were determined not to have a stroke.

The difference between groups did not reach statistical significance, and the study was not powered to assess less than a 14% difference between groups. Safety outcomes were similar between groups, however, and statistical trends toward better outcomes with uric acid in this proof-of-concept trial are enough to justify a study of 1,500 patients to determine whether this is a useful treatment, said Dr. Chamorro, director of the comprehensive stroke center at Hospital Clinic of the University of Barcelona (Spain).

If the results are validated in subsequent trials, it could mean that for every 14 patients given uric acid for acute stroke, 1 patient would become completely free of stroke symptoms, he said in an interview. Uric acid, a potent antioxidant, is thought to help in stroke by inhibiting free radicals that are created during loss of blood flow and that damage brain cells. Uric acid is being explored by other investigators as a treatment for Parkinson’s disease, he added.

All patients in the Urico-ictus Study were treated with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of acute ischemic stroke symptom onset and randomized to receive a single IV infusion of 1 g uric acid dissolved in vehicle or to a control group whose IV infusion contained the vehicle alone (500 mL containing 0.1% lithium carbonate and 5% mannitol). All patients had a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 6 but less than 25, a modified Rankin Scale (mRS) score no greater than 2 prior to the stroke, and a cranial CT showing the absence of blood in the CNS.

The primary results showed modified Rankin Scale scores of 0-1 (or 2 if premorbid was 2) at 90 days in 39% on uric acid and 33% on placebo (P = .099).

Among secondary outcomes, the median mRS was 2 in the uric acid group and 3 on placebo (P = .045), suggesting a trend toward greater effectiveness with uric acid. A 1-point absolute reduction in median mRS is similar to the effects seen in the first trials of thrombolytic therapy, Dr. Chamorro pointed out.

Patients on uric acid were significantly less likely to show worsening at day 3 compared with the placebo group (3% vs. 9%). The uric acid group showed a "high statistical trend" toward having fully independent functioning at 90 days as assessed by a score greater than 94 on the Barthel Index of Activities of Daily Living, with 48% on uric acid and 41% on placebo reaching this mark, Dr. Chamorro reported at the meeting, sponsored by the American Heart Association.

Thirteen percent on uric acid and 16% on placebo died within 90 days. Gout occurred within 90 days in 0.5% on uric acid and 2% on placebo. The proportions of patients with an intracranial hemorrhage whose NIHSS score worsened by 4 points within the first 36 hours of treatment were 4% in the uric acid group and 3% in the placebo groups. These safety outcomes did not differ significantly between groups.

Preplanned subgroup analyses showed trends toward greater effectiveness of uric acid in women, patients with high blood glucose levels, or those with moderate strokes, compared with placebo.

Oxidative stress in patients with ischemic stroke contributes to brain damage. The antioxidant properties of uric acid proved to be neuroprotective in animal studies. Dr. Chamorro and his associates reported in a previous prognostic study of 881 patients with acute ischemic stroke that each milligram per deciliter increase in serum uric acid was associated with a 12% increase in the odds of a good clinical outcome (Stroke 2002;33:1048-52). Previous animal studies suggest uric acid may help reduce stroke sequelae.

Dr. Chamorro and his coauthors reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert