Stroke has become the second leading cause of death in industrialized nations, and remains a major cause of morbidity. As demonstrated by the use of thrombolysis, rapid intervention after the onset of a stroke can limit neurologic damage and improve outcomes. Thrombolysis, the only approved treatment for acute ischemic stroke, must be initiated within the first three hours after stroke onset and may be extended up to six hours with intra-arterial administration. This brief time window and a perceived risk of hemorrhage, however, have limited its application to less than five percent of patients presenting with an acute stroke. Therefore, emphasis has been placed on the development of clinically efficacious neuroprotectants with the potential to alter the course of this condition. A major contributor to brain injury after stroke is tissue oxidation by free radicals. To address this, NXY- 059, a free-radical-trapping agent, was developed and subsequently shown to reduce infarct size and preserve brain function in animal models of acute ischemic stroke. In an effort to translate these finding to the clinical arena, Lees and colleagues published the results of the Stroke-Acute Ischemic NXY Treatment (SAINT I) study investigating the ability of a free-radicaltrapping agent, NXY-059, to reduce the morbidity of acute ischemic stroke (N Engl J Med 354:588–600, 2006). One thousand twenty-two patients underwent randomization in this double-blinded, placebo-controlled trial. Patients with a clinical diagnosis of acute stroke commencing no earlier than six hours prior to study entry were randomly assigned to receive an intravenous infusion of either NXY-059 or placebo. Results were as follows: Of the 1722 patients who underwent randomization, 1699 were included in the efficacy analysis. Of these 1699 patients, 850 received NXY-059 and 849 received placebo, with the two study groups being comparable in regard to baseline prognostic variables. In the treatment group, the distribution of scores on the modified Rankin scale for the primary endpoint of disability at 90 days was improved, as compared to placebo (P=0.038). Furthermore, an additional 3.7 percent and 4.4 percent of patients in the NXY-059 group recovered the ability to walk and were completely cured, respectively. Consistent with findings at 90 days, the study drug improved outcomes at 7 and 30 days. Importantly, there was no difference between the two groups in any adverse event and no significant change in routine laboratory values. Of note, NXY-059 had no effect on the pre-specified co-primary neurologic end point, the change from the baseline National Institutes of Health Stroke Scale (NIHSS), as the difference between the two groups was only 0.1 point (95 percent confidence interval, −1.4 to 1.1; P=0.86). Mortality was also unaltered by treatment with NXY-059 (17 percent died in the treatment group versus 16.6 percent in the placebo group). Symptomatic hemorrhagic transformation, the major complication associated with thrombolysis, occurred in only 2.5 percent of patients who received NXY-059 versus 6.4 percent of those assigned to placebo (P=0.036). This trial succeeded in demonstrating a benefit for NXY-059 in acute ischemic stroke through a reduction in disability at 90 days. In addition, there was no statistically significant association between the investigational drug's efficacy and stroke severity or time from the onset of stroke to treatment, indicating that therapeutic benefit is preserved irrespective of these factors. The authors' findings are further strengthened by the use of the modified Rankin scale, which is robust and reflects aspects of stroke recovery that are directly relevant to quality of life and daily activities. Extrapolating the results to a dichotomized outcome approach, the number of patients needed to treat would be 22 to produce cure or 27 to restore ambulation after stroke. If the results according to scores on the modified Rankin scale are confirmed, even a moderate overall benefit would be clinically important given the disabling nature of stroke and its substantial social cost. In summary, these findings support alteration of the free radical cascade as a promising avenue for the development of neuroprotective agents. Confirmatory data will hopefully emerge from the ongoing follow-up investigation, SAINT II, that was expanded to include 3200 patients. These data will ultimately determine whether investigators have finally identified the first successful neuroprotectant drug for stroke victims. If so, the significance of these findings go way beyond the benefits afforded by this particular agent but demonstrate that neuroprotectant drug development is possible after decades of failure. RICARDO J. KOMOTAR, M.D. BRAD E. ZACHARIA, B.S. E. SANDER CONNOLLY, JR., M.D. CLINICAL RESEARCH
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May 22, 2023
Daniela De Almeida Souza + 5
Open Access
