Optimizing endovascular therapy for ischemic stroke

Overview

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.

Print Overview and Timeline(pdf, 554 KB) 

Timeline

1973-1980

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.

NIH logo NINDS logo
Penumbra Core Illustration
NINDS
1988-2000

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

NIH logo NINDS logo
Magnetic resonance angiography (MRA). Courtesy Creative Commons
Creative Commons
1989-1993

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

NIH logo NINDS logo
1991-1995

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.

NIH logo NINDS logo
DWI is adapted for use in stroke patients and combined with perfusion imaging. iStock|©kali9
iStock|©kali9
1991-1995

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.

1995

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.

NIH logo NINDS logo
1996-2004

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.

NIH logo NINDS logo
2003-2011

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
2005

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.

NIH logo NINDS logo
2011

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.

NIH logo NINDS logo
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
2012

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.

NIH logo NINDS logo
2014

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
2016

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.

NIH logo NINDS logo
2016

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.

NIH logo NINDS logo
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.

List of References

  1. Benjamin EJ, et al, and the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the  American Heart Association. Circulation. 2018 Mar 20;137(12):e67-e492. doi: 10.1161/CIR.0000000000000558. Epub 2018 Jan 31. Review. Circulation. 2018 Mar 20;137(12 ):e493. PMID: 29386200

  2. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992 Jul;32(1):78-86. PMID: 1642475

  3. Malhotra K, Gornbein J, Saver JL. Ischemic Strokes Due to Large-Vessel Occlusions Contribute Disproportionately to Stroke-Related Dependence and Death: A Review. Front Neurol. 2017 Nov 30;8:651. doi: 10.3389/fneur.2017.00651. eCollection 2017. Review. PMID: 29250029

  4. Symon L, Pasztor E, Branston NM. The distribution and density of reduced cerebral blood flow following acute middle cerebral artery occlusion: an experimental study by the technique of hydrogen clearance in baboons. Stroke. 1974 May-Jun;5(3):355-64. PMID: 4209598 (UK, Medical Research Council and the Wellcome Foundation)

  5. Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia - the ischemic penumbra. Stroke. 1981 Nov-Dec;12(6):723-5. PMID: 6272455 (editorial)

  6. Thresholds of focal cerebral ischemia in awake monkeys. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. J Neurosurg. 1981 Jun;54(6):773-82. PMID: 7241187 (NIH/NINDS, grants NS13165, NS10828, and NS11001)

  7. Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, Wienhard K. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab. 1992 Mar;12(2):193-203. PMID: 1548292 (Germany)

  8. Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke. 1996 Apr;27(4):599-606. PMID: 8614914 (France, CNAM-INSERM grant 82/90)

  9. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998 Jan;29(1):4-11. PMID: 9445320 (Abbott Laboratories)

  10. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999 Dec 1;282(21):2003-11. PMID: 10591382 (Abbott Laboratories)

  11. Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, Starkman S, Grotta J, Spilker J, Khoury J, Brott T. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999 Dec;30(12):2598-605. PMID: 10582984 (Genentech)

  12. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004 Apr;35(4):904-11. Epub 2004 Mar 11. PMID: 15017018 (NIH/NINDS, grant NS39160)

  13. IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007 Jul;38(7):2127-35. Epub 2007 May 24. PMID: 17525387 (NIH/NINDS, grant NS39160)

  14. Smith WS. Technology Insight: recanalization with drugs and devices during acute ischemic stroke. Nat Clin Pract Neurol. 2007 Jan;3(1):45-53. Review. PMID: 17205074 (review)

  15. Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, Lutsep HL, Nesbit GM, Grobelny T, Rymer MM, Silverman IE, Higashida RT, Budzik RF, Marks MP; MERCI Trial Investigators. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005 Jul;36(7):1432-8. Epub 2005 Jun 16. PMID: 15961709 (Concentric Medical)

  16. FDA. 510(k) Premarket Notification Database. Merci Retriever. Retrieved from https://www.accessdata.fda.gov/cdrh_docs/pdf3/K033736.pdf.

  17. Balasubramaian A, Mitchell P, Dowling R, Yan B. Evolution of Endovascular Therapy in Acute Stroke: Implications of Device Development. J Stroke. 2015 May;17(2):127-37. doi: 10.5853/jos.2015.17.2.127. Epub 2015 May 29. Review. J Stroke. 2015 Sep;17(3):379. PMID: 26060800 (review)

  18. Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):914-23. doi: 10.1056/NEJMoa1212793. Epub 2013 Feb 8. PMID: 23394476; NCT00389467 (NIH/NINDS, grant P50 NS044378)

  19. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013 Mar 7;368(10):893-903. doi: 10.1056/NEJMoa1214300. Epub 2013 Feb 7. PMID: 23390923; NCT00359424 (NIH/NINDS, grants NS052220, NS054630, and NS077304; Genentech; EKOS; Concentric Medical; Cordis Neurovascular; and Boehringer Ingelheim)

  20. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E; SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):904-13. doi: 10.1056/NEJMoa1213701. Epub 2013 Feb 6. PMID: 23387822; NCT00640367 (Italian Medicines Agency)

  21. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. doi:  10.1056/NEJMoa1411587. Epub 2014 Dec 17. PMID: 25517348 (Dutch Heart Foundation; grants from AngioCare Covidien/ev3, Medac/Lamepro, and Penumbra)

  22. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015 Mar 12;372(11):1019-30. doi: 10.1056/NEJMoa1414905. Epub 2015 Feb 11. PMID: 25671798;  NCT01778335 (Covidien; University of Calgary; Alberta Innovates–Health Solutions; the Heart and Stroke Foundation of Canada; Alberta Health Services)

  23. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, Yan B, Dowling RJ, Parsons MW, Oxley TJ, Wu TY, Brooks M, Simpson MA, Miteff F, Levi CR, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Priglinger M, Ang T, Scroop R, Barber PA, McGuinness B, Wijeratne T, Phan TG, Chong W, Chandra RV, Bladin CF, Badve M, Rice H, de Villiers L, Ma H, Desmond PM, Donnan GA, Davis SM; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015 Mar 12;372(11):1009-18. doi: 10.1056/NEJMoa1414792. Epub 2015 Feb 11. PMID: 25671797; NCT01492725 (Australian National Health and Medical Research Council of Australia; Royal Australasian College of Physicians; Royal Melbourne Hospital Foundation; the National Heart Foundation of Australia; National Stroke Foundation of Australia; Covidien)

  24. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, Albers GW, Cognard C, Cohen DJ, Hacke W, Jansen O, Jovin TG, Mattle HP, Nogueira RG, Siddiqui AH, Yavagal DR, Baxter BW, Devlin TG, Lopes DK, Reddy VK, du Mesnil de Rochemont R, Singer OC, Jahan R; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015 Jun 11;372(24):2285-95. doi: 10.1056/NEJMoa1415061. Epub 2015 Apr 17. PMID: 25882376; NCT01657461 (Covidien)

  25. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Román L, Serena J, Abilleira S, Ribó M, Millán M, Urra X, Cardona P, López-Cancio E, Tomasello A, Castaño C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Pérez M, Goyal M, Demchuk AM, von Kummer R, Gallofré M, Dávalos A; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015 Jun 11;372(24):2296-306. PMID: 25882510; NCT01692379 (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien; Spanish Ministry of Health; Generalitat de Catalunya)

  26. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, Johnston KC, Johnston SC, Khalessi AA, Kidwell CS, Meschia JF, Ovbiagele B, Yavagal DR; American Heart Association Stroke Council. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015 Oct;46(10):3020-35. doi: 10.1161/STR.0000000000000074. Epub 2015 Jun 29. PMID: 26123479

  27. Lev MH, Nichols SJ. Computed tomographic angiography and computed tomographic perfusion imaging of hyperacute stroke. Top Magn Reson Imaging. 2000 Oct;11(5):273-87. Review. PMID: 11142626 (review)

  28. Lev MH, Farkas J, Rodriguez VR, Schwamm LH, Hunter GJ, Putman CM, Rordorf GA, Buonanno FS, Budzik R, Koroshetz WJ, Gonzalez RG. CT angiography in the rapid triage of patients with hyperacute stroke to intraarterial thrombolysis: accuracy in the detection of large vessel thrombus. J Comput Assist Tomogr. 2001 Jul-Aug;25(4):520-8. PMID: 11473180 (NIH/NINDS, grant NS34626; NIH/NCRR, grant RR13213; GE Medical Systems; Radiological Society of North America)

  29. Magnetic resonance imaging in acute stroke: clinical perspective. Oliveira-Filho J, Koroshetz WJ. Top Magn Reson Imaging. 2000 Oct;11(5):246-58. Review. PMID: 11142624 (review)

  30. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, Asgari H, Norman D. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. AJNR Am J Neuroradiol. 1990 May;11(3):423-9. PMID: 2161612 (funding source not stated)

  31. Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy. Magn Reson Med. 1990 May;14(2):330-46. PMID: 2345513 (NIH/NINDS, grant NS014543; NIH/NIGMS, grant GM34767; Fulbright Scholarship)

  32. Mintorovitch J, Moseley ME, Chileuitt L, Shimizu H, Cohen Y, Weinstein PR. Comparison of diffusion- and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats. Magn Reson Med. 1991 Mar;18(1):39-50. PMID: 2062240 (funding source not stated)

  33. Minematsu K, Li L, Fisher M, Sotak CH, Davis MA, Fiandaca MS. Diffusion-weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia. Neurology. 1992 Jan;42(1):235-40. PMID: 1370863 (Harrington Neurological Research Fund; University of Massachusetts)

  34. Knight RA, Dereski MO, Helpern JA, Ordidge RJ, Chopp M. Magnetic resonance imaging assessment of evolving focal cerebral ischemia. Comparison with histopathology in rats. Stroke. 1994 Jun;25(6):1252-61; discussion 1261-2. Stroke 1994 Sep;25(9):1887. PMID: 8202989 (NIH/NINDS, grants NS23393 and NS29463)

  35. Warach S, Chien D, Li W, Ronthal M, Edelman RR. Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology. 1992 Sep;42(9):1717-23. Erratum in: Neurology 1992 Nov;42(11):2192. PMID: 1513459 (funding source not stated)

  36. Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol. 1995 Feb;37(2):231-41. PMID: 7847864 (NIH/NINDS, grant NS001634; Harcourt General Charitable Foundation

  37. Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab. 1996 Jan;16(1):53-9. PMID: 8530555 (NIH/NINDS, grant NS001634; Harcourt General Charitable Foundation)

  38. Sorensen AG, Buonanno FS, Gonzalez RG, Schwamm LH, Lev MH, Huang-Hellinger FR, Reese TG, Weisskoff RM, Davis TL, Suwanwela N, Can U, Moreira JA, Copen WA, Look  RB, Finklestein SP, Rosen BR, Koroshetz WJ. Hyperacute stroke: evaluation with combined multisection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology. 1996 May;199(2):391-401. PMID: 8668784 (NIH/NCI, CA40303 and CA48729; Radiological Society of North America; GE Medical Systems)

  39. Barber PA, Darby DG, Desmond PM, Yang Q, Gerraty RP, Jolley D, Donnan GA, Tress BM, Davis SM. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology. 1998 Aug;51(2):418-26. PMID: 9710013 (Australia)

  40. Thijs VN, Adami A, Neumann-Haefelin T, Moseley ME, Marks MP, Albers GW. Relationship between severity of MR perfusion deficit and DWI lesion evolution. Neurology. 2001 Oct 9;57(7):1205-11. PMID: 11591836 (NIH/NINDS, grants NS34088 and NS35959)

  41. Baird AE, Benfield A, Schlaug G, Siewert B, Lövblad KO, Edelman RR, Warach S. Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann Neurol. 1997 May;41(5):581-9. PMID: 9153519 (NIH/NINDS, grant number not provided; American Heart Association; Harcourt General Charitable Foundation; The Friends of Beth Israel Hospital; Pfizer Inc.)

  42. Parsons MW, Barber PA, Chalk J, Darby DG, Rose S, Desmond PM, Gerraty RP, Tress BM, Wright PM, Donnan GA, Davis SM. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol. 2002 Jan;51(1):28-37. PMID: 11782981 (Australia)

  43. Schellinger PD, Jansen O, Fiebach JB, Heiland S, Steiner T, Schwab S, Pohlers O, Ryssel H, Sartor K, Hacke W. Monitoring intravenous recombinant tissue plasminogen activator thrombolysis for acute ischemic stroke with diffusion and perfusion MRI. Stroke. 2000 Jun;31(6):1318-28. PMID: 10835451 (Germany)

  44. Röther J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, Szabo K, Junge-Hülsing GJ, Hennerici M, Zeumer H, Sartor K, Weiller C, Hacke W; Kompetenznetzwerk Schlaganfall Study Group. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke <6 hours. Stroke. 2002 Oct;33(10):2438-45. PMID: 12364735 (Germany)

  45. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer  M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S; DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005 Jan;36(1):66-73. Epub 2004 Nov 29. PMID: 15569863 (PAION GmbH, Aachen, Germany)

  46. Warach S, Al-Rawi Y, Furlan AJ, Fiebach JB, Wintermark M, Lindstén A, Smyej J, Bharucha DB, Pedraza S, Rowley HA. Refinement of the magnetic resonance diffusion-perfusion mismatch concept for thrombolytic patient selection: insights from the desmoteplase in acute stroke trials. Stroke. 2012 Sep;43(9):2313-8. doi: 10.1161/STROKEAHA.111.642348. Epub 2012 Jun 26. PMID: 22738918 (H. Lundbeck A/S, Valby, Denmark)

  47. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP; DEFUSE Investigators. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006 Nov;60(5):508-17. PMID: 17066483 (NIH/NINDS, grants NS39325, NS044848)

  48. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM; EPITHET investigators. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008 Apr;7(4):299-309. doi: 10.1016/S1474-4422(08)70044-9. Epub 2008 Feb 28. PMID: 18296121 (National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia)

  49. Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG, Wilder MJ, Lutsep HL, Czartoski TJ, Bernstein RA, Chang CW, Warach S, Fazekas F, Inoue M, Tipirneni A, Hamilton SA, Zaharchuk G, Marks MP, Bammer R, Albers GW; DEFUSE 2 study investigators. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol. 2012 Oct;11(10):860-7. PMID: 22954705 (NIH/NINDS, grants NS03932505, NS051372, and intramural NS003043)

  50. FDA. 510(k) Premarket Notification Database. iSchemaView RAPID. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K182130.

  51. Lansberg MG, Christensen S, Kemp S, Mlynash M, Mishra N, Federau C, Tsai JP, Kim S, Nogueria RG, Jovin T, Devlin TG, Akhtar N, Yavagal DR, Haussen D, Dehkharghani S, Bammer R, Straka M, Zaharchuk G, Marks MP, Albers GW; CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project (CRISP) Investigators. Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke. Ann Neurol. 2017 Jun;81(6):849-856.  PMID: 28486789 (NIH/NINDS, grants NS086487, NS07520902)

  52. Broderick JP, Palesch YY, Janis LS; National Institutes of Health StrokeNet Investigators. The National Institutes of Health StrokeNet: A User's Guide. Stroke. 2016 Feb;47(2):301-3. doi: 10.1161/STROKEAHA.115.011743. Epub 2015 Dec 29. PMID: 26715457

  53. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. doi: 10.1056/NEJMoa1713973. Epub 2018 Jan 24. PMID: 29364767 (NIH/NINDS, grants NS086487 and NS092076)

  54. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG; DAWN Trial Investigators. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. doi: 10.1056/NEJMoa1706442. Epub  2017 Nov 11. PMID: 29129157; NCT02142283 (Stryker Neurovascular)

  55. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL; American Heart Association Stroke Council. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110. doi: 10.1161/STR.0000000000000158. Epub 2018 Jan 24. Review. Stroke. 2018 Mar;49(3):e138. Stroke. 2018 Apr 18; PMID: 29367334

  56. Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators; the EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046. PMID: 31067369 (Australian National Health and Medical Research Council and others; NCT00887328 and NCT01580839.)

  57. Multi-arm Optimization of Stroke Thrombolysis (MOST) (2019). Retrieved from https://clinicaltrials.gov/ct2 (Identification No. NCT03735979)