Should uric acid be administered alongside thrombolysis for stroke patients?

The most effective treatment approach in acute ischemic stroke is early reperfusion. Current reperfusion therapies include the intravenous administration of the recombinant tissue plasminogen activator (rtPA) within 4ʹ5 h from stroke onset, and/or the use of endovascular thrombectomy within 6 h from stroke onset [1]. The aim of these therapies is to restore anterograde perfusion and salvage ischemic brain by reopening the occluded artery. Early reperfusion is associated with a significant increase in the odds of good functional outcome at long term and a significant reduction in the risk of death, although less than half of those who are finally treated obtain permanent benefits [1]. In the case of effective vessel recanalization, the lack of favorable response may be related to fast infarct progression before recanalization, downstream embolization, and the so-called ‘reperfusion injury’. Actually, recanalization itself may partially outweigh the beneficial effects of reperfusion by promoting increased oxidative stress related to the return of oxygen to a severely ischemic tissue [2].

Oxidative stress is one of the main mechanisms implicated in the physiopathology of ischemic stroke. The ischemic brain is particularly susceptible to oxidative stress compared with other organs due to its high consumption of oxygen and its relatively low antioxidant capacity. Immediately after the onset of brain ischemia, a rapid increase of oxidative stress mediators occurs. During reperfusion, oxidative stress reaches higher peaks that may overwhelm the scavenging capacity of endogenous antioxidant systems. This surge of oxidative stress begins early after the onset of ischemia, increases sharply and rapidly after reperfusion, and lasts for at least 6–12 h [3]. Accordingly, in patients with acute stroke, the endogenous antioxidant capacity decreases, and this decrease is related to poor clinical and radiological outcomes [4]. Overall, preclinical and clinical data support the amplification of the antioxidant capacity by the administration of antioxidant molecules, such as uric acid (UA), as a potentially effective neuroprotective strategy [5].

In humans, UA is the main endogenous antioxidant in blood [6]. UA has a number of strong antioxidant properties, which include scavenging of hydroxyl radicals, hydrogen peroxide, and peroxynitrite, and the prevention of lipid peroxidation [7]. Humans have higher UA levels than most mammals, an observation that has been interpreted as an evolutionary advantage for early primates due to the antioxidant protection afforded by UA against longevity-related diseases or cancer [6]. Given the strong antioxidant properties of UA, several experimental studies have evaluated the neuroprotective effect of the exogenous administration of UA in different disease models, including experimental brain ischemia [7–9]. Thus, in models of brain ischemia in rats that involve permanent or transient mechanical occlusion of the middle cerebral artery (MCA), the administration of UA reduces brain damage [7]. Moreover, in the rat thromboembolic model, UA administration is also neuroprotective, and the combination of UA and rtPA shows synergistic effects in relevant outcome measures, that include reduced infarct volume, improved behavior, and reduced neutrophil infiltration and oxidative stress–related tissue hallmarks such as tyrosine nitration [8]. These protective effects are also apparent in the prevention of morphological changes driven by oxidative stress in the ischemic cerebral arteries, particularly when a hyperemic response occurs after reperfusion [9].

The potential value of the administration of UA is also supported by observational studies in patients with acute ischemic stroke, and by randomized phase II studies. Several observational studies have shown an independent association between elevated UA levels and cardiovascular morbidity and mortality, including an increased risk of stroke. It has been suggested that UA can promote endothelial dysfunction through pro-oxidant and inflammatory mechanisms, as well as aspirin resistance [10]. Nevertheless, the relationship between UA and the risk of stroke should be separated from the potential neuroprotective effects of UA replenishment in conditions of enhanced exposure to oxidative stress, such as acute brain ischemia. In patients with acute stroke, the link between higher UA levels and clinical outcome has shown contradictory results, varying from no association with clinical prognosis to association with improved or worse functional outcome (reviewed in [5]). Of note, a recently published systematic review and meta-analysis including 8131 patients from 10 different studies showed that higher serum UA levels were consistently associated with better long-term clinical outcome [11]. Indeed, UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with reduced infarct growth at follow-up and with better recovery [12]. Reassuringly, in acute stroke patients treated with systemic alteplase, lower UA levels are associated with an increased risk of malignant MCA infarction and of hemorrhagic transformation [13]. Additionally, arterial recanalization is associated with more remarkable reductions of serum UA levels that are paralleled by an increase of circulating allantoin levels, a product of the oxidation of UA [14]. Overall, these data confer biological plausibility of the hypothesis that UA replenishment after acute stroke onset may be of clinical value.

The exogenous administration of UA in acute stroke patients concomitantly treated with thrombolysis has been evaluated in two different clinical trials [15–17]. A phase II randomized placebo-controlled trial demonstrated that the intravenous administration of UA (500 or 1000 mg) alongside with rtPA was safe and prevented an early decrease of endogenous circulating UA levels [15]. Moreover, UA prevented the increase in the circulating levels of the lipid peroxidation marker malondialdehyde, and of active matrix metalloproteinase (MMP)-9, a marker of blood–brain barrier disruption [15,16]. Importantly, the increase in MMP-9 levels was highly correlated with a worse clinical outcome at 3 months [16]. These data lead to the design of the pivotal Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (URICO-ICTUS) trial [17]. The URICO-ICTUS was a moderately sized multicenter, randomized, double-blind, placebo-controlled trial designed to assess the neuroprotective effect of UA in combination with intravenous rtPA (versus rtPA alone) in acute ischemic stroke patients receiving rtPA within 4ʹ5 h of stroke onset. In this phase IIb trial, the administration of UA was safe and did not increase mortality, the incidence of bleeding complications, gouty attacks, or any other adverse events compared with placebo. In the trial, a total of 39.3% of 211 patients treated with UA and 33.0% of 200 patients treated with placebo achieved an excellent outcome at 90 days (relative risk: 1.22; 95% confidence intervals: 0.96–1.56; p = 0.099) [17]. Thus, in comparison with placebo, adding UA to rtPA resulted in a nonsignificant increase of 6.3% on the rate of excellent outcome at 90 days. Albeit not being significant due to the limited sample size of the trial, this treatment effect fell within the absolute effect sizes of 2–8% that the Stroke Therapy Academic Industry Roundtable considers acceptable for neuroprotective therapies [18]. Consistently, UA therapy was also followed by a significant decrease in residual disability and a shift toward better scores in the ordinal distribution of the modified Rankin scale [17]. Importantly, the statistical analysis plan of the URICO-ICTUS trial included predefined analyses to assess the effect of UA therapy in several subgroups of patients defined by relevant baseline conditions, such as age, sex, stroke severity, or pretreatment glucose. Hence, UA therapy improved clinical outcome in patients with pretreatment hyperglycemia [17,19], in females [17,20], and in patients with moderate strokes [17]. In relation to sex differences, women had lower concentration of UA than men at baseline, and UA levels were persistently lower in women allocated to the placebo group. At the end of UA infusion, women disclosed a greater allantoin to UA ratio, especially in those with reduced infarct growth, suggesting a greater exposition to the effects of free radicals and a more efficient nonenzymatic oxidative consumption of UA [20]. Additionally, UA therapy was able to reduce infarct growth when early recanalization was achieved after thrombolytic therapy, but not in the case of delayed or no recanalization [19]. Overall, these observations suggest that the benefit of UA as a neuroprotective agent may be greater in circumstances of low baseline endogenous antioxidant capacity (females) or higher exposure to oxidative stress, such as in conditions of hyperglycemia or early reperfusion.

The very recent emergence of positive clinical trials showing the efficacy of endovascular reperfusion therapy gives a new window of opportunity for the demonstration of the ultimate benefits of neuroprotective therapies in humans. The combination of rapid reperfusion and neuroprotective therapies would be of added value for maximizing the beneficial effects of rapid reperfusion and to reduce the harmful consequences of reperfusion injury after recanalization. The benefits of this combined approach may be heightened in patients with good collateral circulation, a condition in which the arrival of the neuroprotectant drug to the ischemic tissue may be enhanced while successful reperfusion is achieved. As commented in this editorial, a number of evidences support the value of the addition of UA to reperfusion therapies. Given the encouraging preclinical and clinical data regarding the potential neuroprotective effects of UA administration in brain ischemia, the question whether UA should be administered alongside reperfusion therapies in acute stroke patients is clearly warranted and urges for the implementation of adequately powered confirmatory clinical trials.

Financial and competing interests disclosure

Á Chamorro is inventor of the patent “Pharmaceutical composition for neuroprotective treatment in patients with ictus comprising citicoline and uric acid” and whose proprietor is Hospital Clinic i Provincial of Barcelona, Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Notes on contributors

Sergio Amaro

Ángel Chamorro