The Lancet Neurology Publishes 5-Year Follow-Up Data of ISAT


May 26, 2009—In the May issue of The Lancet Neurology, Andrew J. Molyneux, MD, et al published findings from a study that aimed to assess the long-term risks of death, disability, and rebleeding in patients randomly assigned to clipping or endovascular coiling after rupture of an intracranial aneurysm in the follow-up of the International Subarachnoid Aneurysm Trial (ISAT) (2009;8:427–433). The UK Medical Research Council funded the study.

From their findings, the investigators concluded that there was an increased risk of recurrent bleeding from a coiled aneurysm compared with a clipped aneurysm, but the risks were small. The risk of death at 5 years was significantly lower in the coiled group than it was in the clipped group. The standardized mortality rate for patients treated for ruptured aneurysms was increased compared with the general population.

According to the investigators, ISAT enrolled 2,143 patients with ruptured intracranial aneurysms between 1994 and 2002 at 43 neurosurgical centers and randomly assigned patients to clipping or coiling. Clinical outcomes at 1 year have been previously reported. All UK and some non-UK centers continued long-term follow-up of 2,004 patients enrolled in the original cohort. Annual follow-up has been done for a minimum of 6 years and a maximum of 14 years (mean follow-up at 9 years). All deaths and rebleeding events were recorded. Analysis of rebleeding was by allocation and by treatment received.

The investigators found that 24 rebleeds had occurred more than 1 year after treatment; of these, 13 were from the treated aneurysm (10 in the coiling group and three in the clipping group; log-rank P = .06 by intention-to-treat analysis). There were 8,447 person-years of follow-up in the coiling group and 8,177 person-years of follow-up in the clipping group. Four rebleeds occurred from a pre-existing aneurysm and six from new aneurysms. At 5 years, 11% (112 of 1,046) of the patients in the endovascular group and 14% (144 of 1,041) of the patients in the neurosurgical group had died (log-rank P = .03). The risk of death at 5 years was significantly lower in the coiling group than in the clipping group (relative risk, 0.77; 95% confidence interval [CI], 0.61–0.98; P = .03), but the proportion of survivors at 5 years who were independent did not differ between the two groups: endovascular 83% (626 of 755) and neurosurgical 82% (584 of 713). The standardized mortality rate, conditional on survival at 1 year, was increased for patients treated for ruptured aneurysms compared to the general population (1.57; 95% CI, 1.32–1.82; P < .0001), reported the investigators.

In related news, on June 3, The Lancet Neurology announced the publication (online ahead of print in the July issue) of a study by Dennis Nieuwkamp, MD, et al that showed that improvements in diagnosis and treatment of aneurysmal subarachnoid hemorrhage (SAH) over the past 30 years is linked to a 17% reduction in the risk of death in those patients.

According to The Lancet Neurology, in high-income countries, SAH affects eight in 100,000 people every year. It causes 5% to 10% of incident stroke cases and is associated with a poor outcome—about 30% of patients die within 24 hours, and of those who survive, more than a quarter are left disabled. Recent advances in diagnosis and treatments—including computed tomography and magnetic resonance imaging techniques for detection of aneurysms, dedicated stroke units, and endovascular coiling of burst aneurysms—have greatly improved the prognosis of patients who reach a hospital in good condition and are suitable candidates for these treatments. However, whether these better diagnostic and management strategies have reduced the risk of death and disability from SAH in the general population was not known. To answer this question, the investigators conducted a meta-analysis of 33 studies involving 8,739 patients from 19 countries in five continents between 1973 and 2002. They adjusted the results for confounding factors such as age and sex and also examined regional differences.

The investigators found that despite an increase in the average age of patients with SAH from 52 to 62 years, the likelihood of dying from an SAH has declined from 51% to 35% over 3 decades—a decrease of 0.6% per year. Adjustment for sex had no effect on the reduced risk of death, and a smaller but not statistically significant decrease was shown after adjustment for age—to 0.4% per year. The investigators also reported that case fatality rates in Japan were significantly lower (11.8%) than in Europe, the United States, Australia, and New Zealand. No other regional differences in case fatality were found. The authors suggest that these regional differences may be the result of variation in the speed of patients' admission to the hospital for the early occlusion of the aneurysm.

As reported by The Lancet Neurology, the investigators concluded that in the future, case fatality after SAH might decrease even more, owing to new diagnostic and therapeutic methods. However, the focus should also be on case morbidity because of the high costs from the loss of productive life-years and the long-term care of patients with SAH who become and remain disabled from a young age. In an accompanying commentary, Rustam Al-Shahi Salman, MD, and Cathie Sudlow, MD, noted that two major challenges remain—aneurysm treatment in the elderly because of the aging population and the delivery of effective interventions for SAH in low- to middle-income countries, which bear the greatest global burden of SAH.

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