Partial Occlusion of Abdominal Aorta May Enhance Cerebral Circulation in Stroke

Daniel M. Keller, PhD

October 20, 2010

October 20, 2010 (Seoul, South Korea) — SENTIS, a randomized trial evaluating augmentation of cerebral perfusion via partial aortic occlusion in patients with acute ischemic stroke, has demonstrated a significant reduction in stroke mortality in the treatment group, although it did not show an improvement on the National Institute of Neurological Disorders and Stroke Global Score, the coprimary outcome of the trial.

The NeuroFlo catheter (CoAxia) that provided the occlusion in this trial appeared to be safe to use beginning up to 14 hours after onset of stroke symptoms and did not significantly increase intracerebral hemorrhage. The trial results suggest that the procedure may benefit some specific patient subgroups.

SENTIS principal investigator Ashfaq Shuaib, MBBS, professor of medicine and director of the Stroke Program at the University of Alberta in Edmonton, Canada, described some of the research leading up to this trial for the audience here at the 7th World Stroke Congress.

Partial Intra-Aortic Occlusion

Large-animal models have demonstrated increased central and intracranial blood flow with partial occlusion of the descending aorta both during the procedure and 90 minutes afterward, Dr. Shuaib said. Small-animal models have shown that partial intra-aortic occlusion can improve perfusion deficits and limit infarct size after experimental focal cerebral ischemia. Finally, human feasibility trials in 29 patients with ischemic stroke demonstrated the safety of the technique, with some trends toward clinical benefit.

The catheter consists of 2 independently controlled balloons positioned above and below the renal arteries and inflated to 70% occlusion for 45 minutes, thereby increasing intracerebral blood flow with minimal increase in central blood pressure.

Dr. Shuaib said the hypothesis for this trial was that the catheter device could augment cerebral collateral circulation and thus limit infarct growth in ischemic stroke, leading to better functional outcomes compared with medical management alone.

SENTIS was a single-blind multinational trial in which 515 patients were randomly assigned 1:1 to receive catheter occlusion treatment or medical therapy alone. One primary endpoint was a return to normal on the National Institute of Neurological Disorders and Stroke Global Score (comprising National Institutes of Health Stroke Scale [NIHSS] scores of 0 - 1, modified Rankin Scale [mRS] scores of 0 - 1, a Barthel Index score of 95, and a Glasgow Outcome Scale score of 5).

A second primary endpoint was serious adverse effects at 90 days. Key secondary endpoints were mRS score of 0 to 2, mortality, and the rate of intracerebral hemorrhages.

Patients were eligible if they were within 14 hours of the onset of symptoms, had an NIHSS score of 5 to 18, and had cortical involvement. There were no imaging criteria beyond noncontrast computed tomography. Exclusion criteria were cardiac or renal dysfunction, intravenous tissue plasminogen activator, intra-arterial interventions, or a stroke covering more than one third of the territory of the middle cerebral artery.

The intention-to-treat population was 230 patients in the treatment group (with 5 crossovers to the control group) and 257 patients in the control group (with 1 crossover to the treatment group). Twelve patients were lost to follow-up, leaving 475 patients with 30- and 90-day data.

Baseline demographics of the groups showed similar age (mean age, 67.5 - 68.3 years; range, 28.7 - 93.4 years in the treatment group and 19.4 - 95.9 years in the control group) and about equal proportions of men and women. The groups were also well-balanced in terms of medical histories. The mean time from onset of symptoms to randomization was 7.6 hours for the treatment group and 7.7 hours for the control participants.

Statistically Nonsignificant

For the primary efficacy endpoint of returning to normal on stroke scales, the odds ratio (OR) was a statistically nonsignificant 1.17 (P = .407). The treatment was safe, and serious adverse events did not differ between the groups, with 43.9% of the patients in the treatment group having serious adverse events within 90 days vs 42.8% in the control group (P = .92).

Stroke-related serious adverse events in the groups were 20.9% and 24.5% for the patients receiving treatment vs patients receiving placebo, respectively (P = .28). There were also no statistical differences in cardiac, renal, vascular, neurological, pulmonary, or gastrointestinal events between the groups.

For secondary endpoints, the treatment did show a benefit in 90-day mortality in the treatment group at 7.4% vs 14.4% for the control patients (log rank P value = .015). Most deaths occurred within the first 20 days. "Importantly, these deaths were not at the expense of severe strokes," Dr. Shuaib said.

The rates of fatal neurological bleeding, edema, stroke progression, new stroke, or fatal systemic events were all less in the treatment group. Serious intracranial hemorrhage at 24 hours was slightly higher in the treatment group (2.6% vs 1.9%), as was symptomatic hemorrhage (1.3% vs 0.8%). At 90 days, the rates of any or serious intracranial hemorrhage were equivalent or slightly less for the treatment group.

The treatment group showed a trend toward benefit for those patients who presented with NIHSS scores of 8 to 13 (n = 190), with an OR of 1.85 (P = .051). Similarly, time from symptom onset of less than 5 hours resulted in an OR of 3.51 in favor of treatment (P = .014). Older age was a predictor of benefit (OR, 1.98 [P = .044] for age 70 years or older; OR, 4.03 [P = .013] for age 80 years or older).

Dr. Shuaib concluded that NeuroFlo treatment, when used up to 14 hours of onset of the stroke, did not significantly increase intracranial hemorrhages — but neither did it show an improvement in the Global Score outcome measure. However, "it demonstrated a significant reduction in stroke mortality in the treatment group," he said.

A post hoc analysis based on mRS scores of 0 to 2 suggested a trend toward a meaningful treatment effect in the total patient population (OR, 1.34), a strong trend toward treatment effect in the NIHSS midrange strokes (OR, 1.85; P = .051), and a significant effect in the population older than 70 years (OR, 1.98; P = .044). Dr. Shuaib said there was also a strong trend to avoidance of mRS scores of 5 or 6 that may be an important additional treatment effect.

He said the investigators are currently stratifying the results according to imaging at presentation, and he believes further study of the technique is warranted.

Promising Technique

Bo Norrving, MD, professor of neurology at Lund University in Sweden, and president of the World Stroke Organization and Congress cochairman, told Medscape Medical News that the SENTIS trial showed "a promising technique. It seems safe, and also it seems to be feasible to do."

He said when the technique first came on the scene, many objected that it may be cumbersome, complicated, and dangerous.

"I think the study shows it's possible to do, it's feasible, and it was safe," Dr. Norrving said. He expects more studies with the NeuroFlo device and speculated that if results are good at 90 days, they should be durable or even augmented in the longer run.

Dr. Shuaib is the principal investigator and chair of the steering committee for SENTIS. He is a consultant to and has received research funding from CoAxia, developer of the NeuroFlo catheter. Dr. Norrving reported that he has received honoraria from Allergan, Bayer, and Boehringer and has done clinical trials work on endpoints committees with Servier, PhotoThera, and Syngis Pharma AG.

7th World Stroke Congress: Plenary III: Large Clinical Trials Closing Session. Presented Saturday, October 16, 2010.

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