Optimizing endovascular therapy for ischemic stroke


A stent-retriever captures a clot blocking an artery in the brain. Credit: Medtronic
A stent-retriever captures a clot blocking an artery in the brain. Credit: Medtronic

Nearly 800,000 people in the U.S. have a stroke each year1. Most of these strokes are ischemic strokes, caused when a clot in a brain artery blocks blood flow, leading to permanent impairment if blood flow is not restored promptly. The clot-busting drug tPA (tissue plasminogen activator) was the first treatment approved for acute ischemic stroke and is an important frontline therapy. However, intravenous (i.v.) tPA must be given within four and a half hours after stroke onset, and it has limited effectiveness in patients with strokes due to clots in large brain arteries, which account for over a third of ischemic strokes and a disproportionately larger fraction of stroke-related death and disability.

With major contributions from NINDS-supported research, a procedure called endovascular thrombectomy now offers another way to restore blood flow and save at-risk brain tissue in people with strokes due to blockages in large brain arteries. In a typical version of the procedure, a catheter is threaded through an artery at the groin, up to the neck, and to the site of a clot in a brain artery. A device called a stent-retriever is guided via the catheter to the clot. There, the operator opens the stent and retrieves the clot into the catheter to restore blood flow. Several endovascular thrombectomy devices are cleared by the FDA for removing clots from the brain, and clinical guidelines provide criteria for their use in carefully selected patients up to 24 hours after stroke symptom onset.

Endovascular thrombectomy has developed alongside advances in brain imaging methods that help physicians determine which patients are most likely to benefit from this treatment. NINDS-supported research was essential to understanding stroke injury progression, developing the first device approved for endovascular thrombectomy, applying novel imaging methods to acute stroke evaluation, and defining brain imaging profiles that, together with time since symptom onset, guide treatment decisions for acute stroke. Urgent medical attention remains imperative for stroke, as increasing numbers of neurons die for every minute of blocked blood flow. However, endovascular devices and sophisticated brain imaging enable good outcomes for more stroke patients and at later times after stroke onset than was once thought possible.

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Studies of brain injury progression after stroke in animal models show that the core lesion is initially surrounded by a penumbra of vulnerable tissue with reduced blood flow4,5,6.

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Penumbra Core Illustration

Magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) are developed and applied to acute stroke diagnosis, offering faster, non-invasive alternatives to conventional angiography for imaging clots and collateral blood vessels in the brain.27,28,29

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Magnetic resonance angiography (MRA). Courtesy Creative Commons
Creative Commons

Diffusion-weighted magnetic resonance imaging (DWI) detects early stroke lesions in in experimental animals30,31,32,33,34.

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DWI is adapted for use in stroke patients and combined with perfusion imaging. This allows rapid imaging of brain tissue already damaged by stroke as well as surrounding areas with low blood flow where tissue is at risk.35,36,37,38.

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 DWI is adapted for use in stroke patients and combined with perfusion imaging. iStock|©kali9

Studies also show variable rates of injury progression after stroke in people. In some cases, viable brain tissue remained in the penumbra 17 hours or more after stroke onset7,8.


FDA approves intravenous tPA as the first treatment for acute stroke, based on results from a clinical trial led by NINDS. Stroke is recognized as a treatable emergency, transforming systems of care and paving the way for additional therapies.

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Using advanced brain imaging, researchers begin to define a profile in stroke patients called mismatch, in which the core lesion seen by DWI or CT scan is smaller than a surrounding area of at-risk tissue detected by perfusion imaging. They predict that patients with this profile will benefit most from treatment to restore blood flow39,40,41,42,43,44,45,46.

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The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) is the first endovascular thrombectomy device cleared by the FDA, for use in stroke patients who are ineligible for or fail to benefit from i.v. tPA. Additional improved devices follow, including the first stent-retrievers in 201215,16,17.

Mechanical Embolus Removal in Cerebral Ischemia (MERCI). Credit: Creative Commons/Neilbarman at English Wikipedia
Creative Commons/Neilbarman at English Wikipedia

The Diffusion and Perfusion Imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study finds patients with the target mismatch imaging profile had the best rates of good clinical outcomes after i.v. tPA treatment between three and six hours after stroke symptom onset47.

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A second NINDS-funded study, DEFUSE 2, finds that patients with the mismatch profile had better outcomes after endovascular therapy than patients without mismatch. DEFUSE 2 used software developed by the investigators for fast, automated analysis of brain imaging scans49.

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DEFUSE 2 used imaging software developed by the investigators for fast, automated analysis of brain imaging scans49. Courtesy of Greg Albers, MD, Stanford University
Courtesy of Greg Albers, MD, Stanford University

A group of clinical trials fails to show better outcomes for endovascular therapy compared to standard medical therapy, including i.v. tPA when appropriate. These trials did not require imaging evidence of large artery occlusion (LAO) or mismatch between perfusion abnormality and tissue already injured 18,19,20.

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Industry-sponsored clinical trials show a benefit for endovascular therapy over medical therapy alone in stroke patients with LAO. The trials used newer stent-retrievers and brain imaging for patient selection, including evidence of LAO in all trials and mismatch in some. The American Heart Association/American Stroke Association adds endovascular thrombectomy within six hours of symptom onset to its guidelines for treating ischemic stroke. 21,22,24,25,26

The American Heart Association/American Stroke Association

The CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project (CRISP) uses computed tomographic (CT) imaging to identify patients with the target mismatch profile and finds good clinical outcomes with endovascular treatment up to 18 hours after symptom onset51.

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Two clinical trials, including DEFUSE 3 funded by NINDS, support the use of endovascular thrombectomy in MRI or CT perfusion imaging-selected stroke patients with large artery blockages as late as 16-24 hours after patients were last known to be well55,56.

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Defuse 3 logo

History of Development

FDA approval of the clot-busting drug tPA in 1996 as the first treatment for acute ischemic stroke revolutionized emergency medical care for stroke. However, intravenous (i.v.) tPA must be administered quickly after symptom onset, and it has limited effectiveness in patients with strokes due blockages in large brain arteries1. Such large artery occlusion (LAO) strokes account for over a third of ischemic strokes and a disproportionately larger fraction of stroke-related death and disability2. Physicians and researchers recognized that building on the success of tPA would require additional ways to restore blood flow to brain tissue affected by stroke.

Understanding injury progression in stroke

When an artery supplying blood to the brain is blocked, as in ischemic stroke, the tissue served by that artery does not get the oxygen and nutrients it needs. In the 1970s and 1980s, researchers with NINDS and other support used experimental animal models of stroke to understand what levels of blood flow were required for brain tissue to function and survive. They began to distinguish a region of irreversible damage after stroke (the infarct or core lesion) from a surrounding zone they called the penumbra, an area with reduced blood flow where tissue is functionally impaired but surviving4,5,6. The core lesion inevitably expands into the penumbra over time without restored blood flow, but studies in animal models and later research in stroke patients suggested that the rate of injury expansion differs across individuals. Although brain cells quickly die if their blood supply remains blocked, other blood vessels in the region, called collaterals, can compensate to varying degrees. In some studies, viable brain tissue remained in the penumbra for 17 hours or more after stroke onset7,8. Identifying and then saving at-risk tissue in the penumbra by restoring blood flow became a primary goal for stroke treatment.

Endovascular therapies for large artery strokes

Multiple studies supported by NINDS and other sources assessed the benefit of administering clot-busting drugs via catheter directly to blockages inside blood vessels in the brain9,10,11,12,13. This intra-arterial approach was based on the idea that direct delivery would allow higher drug concentrations at the blockage site than i.v. delivery, and in turn to more successful degradation of offending clots in large arteries. In the 1950s, case reports began to describe another intuitively attractive alternative: the surgical removal of blockages14. Early attempts used devices designed for other types of surgery, but later devices were designed specifically for removing stroke-causing clots through a procedure called endovascular thrombectomy. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) device (Concentric Medical, California, USA), developed in part with NINDS support, was the first such device cleared by the FDA in 2004, for use in stroke patients who cannot receive or fail to benefit from i.v. tPA15,16. Additional improved devices followed, including stent-retrievers, which both open affected vessels and remove clots. Clinical trials showed that these devices successfully restored blood flow in patients with strokes due to LAO, but they did not compare clinical outcomes versus medical therapy alone17.

In 2013, a group of clinical trials, including the NINDS-supported Interventional Management of Stroke III trial (IMS III), failed to show that endovascular or intra-arterial therapies led to better outcomes than standard medical therapy, including i.v tPA18,19,20. Although disappointing, understanding why the trials failed provided valuable lessons. Only some of the trials used brain imaging to confirm blockages in large arteries, for which endovascular therapies were presumed to be most effective. In addition, over the course of the trials, thrombectomy devices had continued to improve, yet the trials included older versions ultimately shown to be less effective. By the time the negative trials were completed, new trials addressing these and other concerns were already underway. Just two years later, five major trials together established the superiority of endovascular thrombectomy over medical therapy alone for stroke patients with LAO treated within six hours of symptom onset 21,22,23,24,25. Based on these trials, the American Heart Association/American Stroke Association (AHA/ASA) added endovascular thrombectomy using stent-retrievers to clinical guidelines for the early management of acute ischemic stroke26.

Brain imaging guides patient selection for stroke treatment

Advances in brain imaging proved critical to the success of endovascular therapies for stroke. The 1990s brought expanded use of imaging technologies to neuroscience research and clinical neurology, and by this time, computed tomography (CT) and magnetic resonance imaging (MRI) were used in patients with suspected ischemic stroke to rule out hemorrhage or other causes. However, neither CT nor MRI could reliably detect blockages or the extent of damaged or vulnerable brain tissue at early times after stroke symptom onset. NINDS-supported investigators helped apply transformative innovations in these technologies to stroke diagnosis, including the use of CT and MR angiography to visualize intracranial vasculature and detect clots27,28,29. Compared to traditional angiography, these new methods were non-invasive and fast enough to be compatible with emergency evaluation and treatment. In addition, researchers supported by NINDS and NIGMS were the first to use a more recently developed MRI procedure called diffusion-weighted imaging (DWI) to detect early brain injury in experimental models of stroke and follow the progression of stroke lesions over time30,31,32,33,34. An initial demonstration in human stroke patients showed that DWI could identify lesions as early as 105 minutes after stroke onset35. NINDS and NCI supported the efforts of these and other researchers to further adapt DWI for clinical application and combine it with another method called perfusion imaging to detect areas with reduced blood flow36,37,11.

Armed with these imaging tools, NINDS-funded researchers and others began to define a profile in stroke patients called mismatch, in which the area of tissue detected by perfusion imaging (likely representing at-risk tissue in the penumbra) is initially larger than the area seen with DWI (representing irreversible damage in the core lesion). Without treatment, the DWI lesion tended to grow over time into the area seen with perfusion imaging, suggesting that patients with this mismatch on DWI and perfusion imaging had at-risk brain tissue that might be saved with treatment to restore blood flow 39,40. As in previous studies of stroke injury progression, lesion growth into the penumbra varied across individuals and continued in some cases for several hours after the onset of stroke symptoms, hinting that new imaging techniques might allow patients to be selected for treatment based on the state of their injury and not solely on elapsed time41. Early evidence for this idea came from small studies using DWI and perfusion imaging to monitor the effect of i.v. tPA on lesion growth in stroke patients42,43,44 and from a clinical trial testing desmoteplase (an agent similar to tPA), which was the first trial to use DWI-perfusion imaging mismatch to select patients for enrollment45,46. Subsequently, NINDS supported a large, multicenter study called Diffusion and Perfusion Imaging Evaluation For Understanding Stroke Evolution (DEFUSE). DEFUSE investigators treated stroke patients with i.v. tPA three to six hours after symptom onset and found that patients with the mismatch profile had the best rates of good clinical outcomes47. The study also identified imaging profiles associated with little benefit or with increased risk for dangerous intracranial hemorrhage following treatment to restore blood flow. A later study conducted in Australia had similar findings48.

At the time, although the use of endovascular thrombectomy devices was growing, these devices had not been compared to standard medical treatment, including i.v. tPA when appropriate, and questions remained about how to identify which patients might benefit and which could be harmed. In 2012, results from a second NINDS-funded study, DEFUSE 2, showed that patients with the mismatch imaging profile had better outcomes in response to endovascular therapy than patients without mismatch49. DEFUSE 2 employed imaging software developed by the study investigators for fast, automated analysis of brain imaging scans. This software was later commercialized and granted marketing approval by the FDA50 and is among other imaging analysis platforms now widely used in stroke research and care. Besides MRI methods, NINDS-funded researchers and others also refined CT imaging and clinical parameters for identifying the favorable mismatch profile. MRI scanners are not available in all hospitals, and these alternatives could potentially reach more patients. The CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project (CRISP), again funded by NINDS, suggested that CT perfusion is as effective as MRI at selecting patients likely to benefit from endovascular therapy51. Moreover, this study found examples of good clinical outcomes in some patients with the target mismatch profile even when treated up to 18 hours after symptom onset.

A new revolution in stroke treatment and research

These advances set the stage for randomized, controlled clinical trials to assess endovascular treatment in an expanded time window for stroke patients with LAO and the target mismatch profile. In 2015, the NINDS-funded trial DEFUSE 3 began, notably as the first trial designed for StrokeNet52, a new clinical trials network for stroke studies established by NINDS in 2013. DEFUSE 3 enrolled stroke patients six to 16 hours since symptom onset who had the target mismatch profile determined by MRI or CT perfusion imaging. Patients were randomly assigned to receive either standard medical therapy and endovascular therapy or standard medical therapy alone. The trial was halted early in 2017, when an interim analysis showed overwhelmingly that patients in the endovascular thrombectomy group had better outcomes 90 days after treatment. In the final analysis, 45 percent of thrombectomy patients achieved functional independence compared to 17 percent of patients receiving medical therapy alone, and thrombectomy was also associated with improved survival53. Separately, similar results had emerged from an industry-sponsored trial called DAWN (DWI [Diffusion-Weighted Imaging] or CTP [Computed Tomographic Perfusion] Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo). The DAWN trial enrolled patients with symptom onset between six and 24 hours since they were last known well and, compared to DEFUSE 3, used a different definition of mismatch based on imaging and clinical symptoms54.

The DEFUSE 3 and DAWN trials prompted new AHA/ASA guideline updates to expand the time window for endovascular thrombectomy in imaging-selected stroke patients with large artery blockages from six to 24 hours after symptom onset55. Urgent medical attention remains imperative for acute stroke, as irreversible injury progresses with time in all cases, and faster treatment has the best chances of saving at-risk tissue. However, effective endovascular devices and sophisticated brain imaging methods enable good outcomes for more stroke patients than was once thought possible.

These advances are transforming stroke treatment and stimulating new research directions, just as the approval of i.v. tPA did two decades before. NINDS has supported the successful application of telemedicine to acute stroke care. Now, through remote brain imaging review, patients in small or under-resourced hospitals can be considered for transfer to a stroke center for endovascular therapy they may not otherwise receive. Researchers have recently used brain imaging to revisit whether patients with the mismatch profile may benefit from i.v. tPA beyond currently recommended time limits56, and an NINDS-funded clinical trial will assess whether combining tPA with blood thinners will produce better results in stroke patients than tPA alone57. Additional studies focus on developing next-generation thrombectomy devices for clot removal from smaller vessels in the brain and on understanding variation in the brain’s collateral blood vessels and other factors that contribute to slow lesion progression in some patients and rapid irreversible damage in others. Finally, advances in acute stroke treatment have also revived interest in developing neuroprotective and restorative therapies that might complement clot clearance to limit permanent injury after stroke.

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