Functional outcomes in patients treated with intravenous tissue plasminogen activator with or without endovascular therapy after a moderate to severe acute ischemic stroke were not significantly different, and safety outcomes were similar, in a study that was stopped early because of these results.
In the IMS (Interventional Management of Stroke) III study, 40.8% of patients randomized to receive endovascular therapy plus intravenous TPA met the primary endpoint, a measure of functional independence – a modified Rankin score of 2 or less at 90 days – compared with 38.7% among those who had intravenous TPA alone, a difference that was not statistically significant, reported Dr. Joseph Broderick of the University of Cincinnati Neuroscience Institute, and the other IMS III investigators.
Mortality and other safety outcomes were also not significantly different between the two groups of patients in the study, which was stopped early because of futility after 656 of the planned 900 patients had been randomized. The study is being published online on Feb. 7 to coincide with the presentation of the results at the International Stroke Conference (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1214300]).
Referring to the lack of randomized clinical trial data, the authors pointed out that it is uncertain whether endovascular therapy (which includes endovascular pharmacologic thrombolysis and, more recently, the use of stent retrievers) alone or combined with intravenous TPA is a more effective treatment of acute stroke than intravenous TPA alone, "the only proven reperfusion therapy for acute ischemic stroke."
In the study, conducted at 58 centers in the United States, Canada, Australia, and Europe, 434 patients were randomized to endovascular therapy plus intravenous TPA and 222 were randomized to standard treatment with intravenous TPA alone (started within 3 hours of stroke onset). The median age of those enrolled was 68-69 years (range, 23-89 years), a little over half were men, about 14% were black or Hispanic, and the median the National Institute of Health Stroke Scale (NIHSS) score was 16-17 (8-19 is a moderately severe stroke and 20 or greater is a severe stroke At the beginning of the study, only one thrombectomy device had been cleared by the Food and Drug Administration and, as the trial continued, other devices were used as they became cleared for use in the different countries.
In addition to the main finding, there were no differences in the primary outcome among those patients with an NIHSS score of 20 or more, and those with a score of 19 or lower, said the authors, who had hypothesized that endovascular therapy would have greater efficacy in patients with more-severe strokes since they "have the highest likelihood of occlusion in a major intracranial artery and the greatest volume of ischemic brain at risk."
They had also hypothesized that receiving endovascular therapy earlier would be associated with a greater benefit, but this was also not a significant factor in outcomes.
Mortality at 90 days was 19.1% in the endovascular therapy group and 21.6% in the intravenous TPA–alone group. Within 30 hours of TPA initiation, 6.2% of those on endovascular therapy and 5.9% of those on TPA alone had a symptomatic intracerebral hemorrhage. The differences in mortality at 7 days and in parenchymal hematoma rates were also not significantly different between the two groups. The rate of asymptomatic intracerebral hemorrhage, however, was significantly higher in the endovascular group.
Outcomes consistently trended better with combined therapy in patients with strokes involving larger artery occlusions and those with the shortest times from stroke onset to initiation of treatment, although because of small patient numbers the differences didn’t achieve statistical significance. These will be the subgroups that ought to be the focus of future clinical trials, Dr. Broderick said in a press briefing at the conference.
The underlying rationale for combined therapy is that intravenous TPA can quickly be started in the emergency department while the endovascular device therapy team is assembling, often at another hospital, which entails time-consuming patient transfer.
Intravenous TPA is the only proven therapy for acute ischemic stroke, but endovascular therapy is more effective at achieving recanalization. The study results bore this out: for example, the rate of partial or complete recanalization at 24 hours for an occlusion in the internal carotid artery was 81% with combined therapy compared to 35% with intravenous TPA alone. Yet this higher recanalization rate bore no clinical benefit, possibly because recanalization occurred too late, after ischemia had turned into infarction, Dr. Broderick explained.
"ISM III is going to be disappointing for a lot of people who are proponents of endovascular therapy. However, there is a light at the end of the tunnel in that there are these subgroups who may benefit," Dr. Brian Silver, who was not involved in the trial, said in an interview.