NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials

<p><b>Background and Purpose:</b> In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.</p> <p><b>Methods:</b> Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.</p> <p><b>Results:</b> An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n = 2438) compared with the placebo group (n = 2456): odds ratio for limiting disability = 1.02; 95% CI, 0.92 to 1.13 (P = 0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.</p> <p><b>Conclusions:</b> NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.</p&gt

Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH).</p> <p><b>Methods:</b> We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index.</p> <p><b>Results:</b> We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4±20.1 mL in the NXY-059 group and 23.3±22.8 mL in the placebo group (mean±SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35).</p> <p><b>Conclusions:</b> NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.</p&gt

Early detection and treatment of spinal epidural metastases: the role of myelography.

Spinal epidural metastases were detected in 75 of 140 cancer patients with back pain who were evaluated prospectively by clinical criteria, spine roentgenography, and bone scan. Fifty-five of the 75 patients with epidural metastases had no evidence of myelopathy when diagnosed. Of the patients diagnosed and treated while still ambulatory, more than 90% remained so. Myelograms were performed in 127 patients to diagnose the 75 with epidural disease. To try to reduce the number of myelograms needed, we attempted to design radiotherapy ports based on clinical symptoms and the plain spine films alone. A port could not be designed for 64 of the 127 patients, either because of diffuse vertebral metastases or a normal plain roentgenogram. A port could be designed for 63 patients, and all epidural disease would have been encompassed in 50 of the 54 patients who had spinal epidural metastases (93%). Most patients with cancer and back pain require myelography for accurate treatment planning. There are, however, situations in which treatment can be determined based on symptoms and plain films alone, with a low risk of missing epidural cancer

Early diagnosis of spinal epidural metastases.

Early signs of spinal cord injury on neurologic examination have been the primary indication to proceed with myelography in patients with possible spinal epidural metastases. With this approach, loss of ambulation occurs in more than one half of the patients. In an attempt to diagnose epidural metastases before the onset of myelopathy, we designed a prospective study based on the development of back pain, a precursor of spinal cord injury in nearly all cancer patients. Eighty-seven patients were studied. A high incidence of epidural metastases was found in patients with myelopathy (78 percent). In addition, patients with radiculopathy alone frequently had epidural tumor (61 percent). In 36 percent of the patients who presented with back pain but who had normal neurologic findings, there was evidence of epidural metastases on myelography; all of those patients had vertebral metastases on plain roentgenogram. Over-all, the plain roentgenogram of the spine correctly predicted the presence or absence of epidural tumor in 83 percent of the patients. Whereas 93 percent of the patients with myelopathy had more than 75 percent myelographic block, this occurred in 53 percent of those with radiculopathy and in only 33 percent of those with back pain and normal neurologic findings. In most cancer patients, spinal epidural metastases are both detectable and significantly less extensive before the onset of spinal cord injury