Stroke, a condition that affects over 750,000 patients a year in the United States, is the fourth leading cause of death, and it remains a challenge for clinicians nationwide. The clot-busting drug, tissue plasminogen activator (tPA), is the only FDA-approved therapy for acute ischemic stroke. Since it came on the market in 1996, many other neuroprotective drugs have been tested but all failed to show efficacy in clinical trials. The result, according to NINDS Director Story Landis, PhD, and Deputy Director Walter J. Koroshetz, MD, is that the pharmaceutical industry has pretty much closed the door on developing stroke therapies.
And it's why the NINDS has made research in stroke a priority. According to Dr. Landis, 17 of 29 clinical trials supported by NINDS this year are in stroke. Many of these have been comparative effectiveness trials, which have a major and immediate impact on medical decision-making. But NINDS also supports a number of epidemiological studies to better understand factors that put people at risk for stroke.
During the AAN meeting, stroke experts gathered to talk about strategies to address those risk factors, prevent stroke, and reduce the damage after brain ischemia or hemorrhage. Discussion was stimulated by the NINDS Request for Information (RFI), a call for input from the stroke community to identify the most important research priorities with the highest scientific and health impact. The deadline for ideas was June 30.
“The RFI is part of a larger stroke research planning effort,” said Dr. Landis. A decade ago, the agency convened the Stroke Progress Review Group (PRG) to develop recommendations for stroke research. The group has taken a comprehensive look at the field and identified progress as well as gaps in research that need addressing. The latest report from the stroke PRG — published on the NINDS web site in January: http://1.usa.gov/MPJxbv — highlighted top priorities for future research that includes making reperfusion therapy “swifter, safer and surer.” The group also called for continued study of neuroprotection after reperfusion.
The RFI will complement the 2012 Stroke PRG report and help working groups comprising representative stroke experts to understand what projects would galvanize the stroke research community. The ideas should have “a high probability of leading to a major advance in our biologic understanding of stroke,” said Dr. Landis. The NINDS accepted ideas from the public, physicians or scientists from inside or outside of the stroke field for research on prevention, acute treatment, and recovery/rehabilitation.
But how will the decisions be made? Some have expressed concerns about the process for prioritizing research — whether it will reflect peer review or decision-making by an NINDS committee.
“This is an important concern and the stroke planning process is actually an attempt to make sure that any major initiatives instituted by NINDS are the product of an open, transparent process driven by experts in the field,” said Dr. Koroshetz. “In addition such an initiative would have to be justified by the overwhelming importance of the scientific goal and the concern that the goal could not be achieved without a major scientific push.”
The Stroke PRG identified important areas of research and the value of these is not diminished in any way by this “second phase” of stroke research planning, he said. “However, as there were multiple recommendations from 16 different Stroke PRG workgroups, many of which require substantial investment, it is best if any choice of key targets for the field are made with the input from experts around the world,” he explained.
Exactly why did the NINDS institute the phase 2 planning process? “For the phase 2 stroke planning we are interested to know if there are research goals worthy of a targeted investment to accomplish what would not otherwise be attained,” Dr. Koroshetz said. “Indeed, there would need to be a strong rationale that the goal could not be best achieved by the NIH standard, investigator-initiated research. In any and all cases, projects would undergo peer review and only if a project were reviewed as outstanding science by review would anything be funded.
“In terms of the process, we have constructed multiple layers of input to optimize the democratic nature of the process,” Dr. Koroshetz continued. “First and foremost, we have the recent stroke PRG reports; second, we have the public RFI; third, we will have three workgroups to help prioritize — one each in prevention, treatment, and recovery — and finally we have a relatively unbiased steering committee to analyze and comment upon the deliberations. The steering committee is a workgroup of the NINDS Advisory Council, which will receive the final report. The Council is advisory to Dr. Landis. There are lots of checks and balances so that the process is not hijacked by any special interest.”
During leadership meetings at the AAN meeting, there was a lot of discussion about the many blows the field has taken in failed neuroprotection trials conducted by industry, said Dr. Koroshetz. There was also talk of the successes, however surprising they were, he added, referring to results from the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial. The study was started to evaluate preventive treatments in symptomatic patients with narrowed intracranial blood vessels. Investigators compared aggressive medical management — routinely coaching patients to ensure they achieved their blood pressure and lipid lowering goals — versus aggressive medical management plus angioplasty combined with stenting. The study was stopped when the NINDS Data Safety Monitoring committee found that patients assigned to aggressive medical management had fewer strokes than those who underwent intracranial stent procedures. Surprisingly, the intensive medical management reduced the stroke risk by half over what was expected based on the previous WASID (Warfarin Aspirin Symptomatic Intracranial Disease) study, said Dr. Koroshetz. [For more about the SAMMPRIS trial, visit Neurology Today's “Intracranial Stenting's Risks Over Medical Therapy Prompt Halt of Major Trial”: http://bit.ly/O8h1hN.]
“This study will change how neurologists manage patients at risk for stroke,” Dr. Koroshetz added. “If we can actually achieve the reduction of those risk factors we know about, the effects would be substantial. We need to change patient behaviors as opposed to just prescribing medications.”
There are a number of interventional studies demonstrating the capability of vascular devices to open up blocked arteries and restore blood flow in acute stroke patients. These have been cleared by the FDA for use and reimbursed by Medicare but this interventional approach has not yet demonstrated that the benefits outweigh the risks.
In May, NINDS announced that the only controlled trial — the Interventional Management of Stroke III Trial — stopped enrollment after an interim analysis by the study's Independent Data and Safety Monitoring Board found that use of a combination intra-arterial therapy plus IV tPA versus IV tPA alone showed no clinically significant difference in outcome for patient in the throes of acute stroke. This was a large study involving 50 centers around the world and included data from 587 patients. The data have yet to be analyzed to determine how in subsequent studies the interventional technique might be refined, and how patients should be chosen who have the greatest probability of benefiting from interventional procedures, said Dr. Koroshetz.
In coming months, look for more updates from the NINDS in this column.