April 27, 2012 (New Orleans, Louisiana) — The Interventional Management of Stroke 3 (IMS 3) trial, which was comparing intravenous (IV) tissue plasminogen activator (tPA) alone with combination tPA and intra-arterial (IA) therapy using intra-arterial tPA or mechanical thrombectomy in stroke patients, has suspended enrollment after crossing a prespecified interim analysis threshold.
That means that even if the study continued, it would not produce the expected result — that combination therapy is superior to tPA alone, said principal investigator Joseph P. Broderick, MD, professor and chairman, neurology, University of Cincinnati, Ohio. "This is not what we had hoped," he told Medscape Medical News.
However, he said, "we remain optimistic about mechanical embolectomy technology; we just need to do a better job" of proving that these devices improve patient outcome.
The IMS 3 is a phase 3, randomized, open-label trial that was to enroll 900 patients with a National Institutes of Health Stroke Scale score of 8 or greater treated within 3 hours. The aim of the study was to examine whether a combined IV and IA approach to recanalization is superior to standard IV recombinant (rt)-PA alone.
The primary outcome is a favorable outcome in terms of functional independence as measured by a Modified Rankin Scale score of 0 to 2 at 3 months. The trial was designed to test whether there is an overall absolute difference of at least 10% in the proportion of a favorable outcome for patients treated with the combined IV/IA approach as compared to those treated with the IV rt-PA only approach.
It's important to note that the study was not put on hold because of safety concerns, said Dr. Broderick. He also emphasized that he and the other investigators remain blinded to the study results and that patient follow-up will continue.
To date, about two thirds of the 900 patients have been enrolled but 10% of these still need to be put into the database, said Dr. Broderick.
The earlier single-group IMS 1 and IMS 2 trials (along with the Penumbra Trial and the French RECANALISE study) demonstrated a strong relationship between time to revascularization and good functional outcome at 3 months. In IMS I and 2, revascularization beyond 6 hours resulted in outcomes similar to those of no revascularization.
Dr. Broderick said it's "critical" to develop clinical trials to determine the place of this technology in practice, defining which patients it should be used for and under what circumstances. "We don't want to stay with the current paradigm."
Three embolectomy devices are approved by the Food and Drug Administration as reperfusion options: MERCI (cleared in 2004), Penumbra (cleared in 2007), and Solitaire (cleared just last month, in March). IV rtPA has been established in trials looking at clinical outcome vs placebo, whereas embolectomy has evidence from only single-group studies because of different regulatory approval criteria for drugs vs devices.
"We know the devices can remove clots, but we need to prove that they improve patient outcome compared to standard therapy," said Dr. Broderick.
Investigators from the 50 sites involved in IMS 3 will be disappointed with the decision to suspend the study, said one of the investigators, Pooja Khatri, MD, associate professor, neurology, University of Cincinnati. "We all expected this trial to show a significant advantage of this therapy in severe strokes."
But the suspension should give investigators some direction, she said. "We're hoping that when we actually look at the data that we'll see certain groups that could have potentially benefited from intra-arterial therapies and that will give us the opportunity to study those in a more focused way."
She added that "it's hard to imagine, based on all the prior data that we've had, that intra-arterial therapies aren't useful in a subset of patients, but clearly the parameters we used in IMS 3 didn't end up showing the effect we expected."
Meanwhile, this technology continues to become increasingly popular. A new study presented here by Dr. Khatri at the American Academy of Neurology's 64th Annual Meeting shows that use of mechanical embolectomy almost doubled in the United States from 2008 to 2010.
From a database that includes payor sources, demographic information, and pharmacy drug utilization information, researchers obtained a sampling of 15% of US hospitals. They identified ischemic stroke cases in patients aged 18 and older in 2008, 2009, and 2010. They also identified reperfusion cases (IV rtPA use and mechanical thrombectomy use) by relevant procedure code, pharmacy records, or hospital billing records.
The study found a steadily increasing proportion of strokes treated with reperfusion therapies. In 2008, 4.1% of 61,096 were treated with such therapies. In 2009 the percentage had risen to 4.7%, and in 2010, the percentage stood at 5.4% (P < .001).
Embolectomy use almost doubled during the course of the study, said Dr. Khatri. The numbers went from 275 in 2008 to 354 in 2009 and to 524 in 2010.
Compared with patients who received rtPa alone, patients having embolectomy tended to be younger (mean, 66.7 years vs 69.5 years), have higher rates of mortality, be treated at larger urban teaching hospitals, be on Medicare, and be white.
Neurologists treated 10% of the 863 cases of embolectomy that were identified by procedure codes from 2008 to 2010. Neurosurgeons treated 23% and radiologists, 60%.
What factors are contributing to the significant increase in use of mechanical embolectomy therapy? According to Dr. Broderick, it reflects practice changes in the United States, with more specialists being trained to use the devices and becoming much more comfortable with them. He also pointed out that hospitals, not just physicians, get reimbursed for the procedure, which could be an additional factor driving their use.
The rising use of mechanical embolectomy therapy may partially explain the difficulties that researchers have encountered in recruiting for randomized trials that investigate mechanical embolectomy therapy. "There's been this issue of the procedure and the therapies getting ahead of the evidence at times," said Dr. Khatri. "Reimbursement and ready availability of the devices [have] likely influenced enrollment in randomized trials."
With the suspension of the IMS 3 trial, another trial — the Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke (THERAPY) — should take on more significance, said Dr. Khatri.
"At this point, this trial becomes more important because it's specifically selecting out a subgroup that is believed to be more likely to show a treatment effect of intra-arterial tPA." This subgroup, she said, has clots that are longer — 8 mm or more. "There's been some evidence that IV tPA doesn't open up those clots," she said.
THERAPY, sponsored by Penumbra Inc and launched in July 2011, is designed to assess the Penumbra System as adjunctive treatment to IV rtPA in patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation. It is a prospective, randomized, concurrent controlled study randomly assigning patients to IV rtPA therapy alone or combined IV rtPA therapy and IA treatment.
Dr. Khatri said she agreed with Dr. Broderick that it's imperative that the effectiveness of mechanical embolectomy be determined in definitive clinical trials. She pointed out that more than half of the patients who are treated with IV tPA remain disabled, "so we need something better."
Dr. Broderick also noted that not all patients meet criteria for tPA and that embolectomy might offer an alternative for these patients.
The study presented here was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke. Dr. Khatri receives research support from the NIH (IMS 3 Executive Committee, NeuroNEXT PI) and Penumbra Inc (THERAPY Trial Neurology PI) and travel support from Genentech as an unpaid consultant.
American Academy of Neurology 64th Annual Meeting. Abstract# S09.004. Presented April 24, 2012.
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Cite this: IMS 3 Trial of Mechanical Embolectomy in Stroke Stopped - Medscape - Apr 27, 2012.