New Breakthrough in Acute Stroke Therapy

New Breakthrough in Acute Stroke Therapy

Acute stroke therapy has finally turned a historic corner. On February 11th, results from four landmark randomized controlled clinical trials were highlighted among numerous studies reported at the International Stroke Conference in Nashville, Tennessee. Each trial, outlined in the table below, demonstrated the striking benefit of catheter-based clot removal to restore blood flow in brain arteries in patients with the most severe strokes. This breakthrough in acute stroke therapy echoes the treatment of heart attacks, where catheter-based treatments to open the occluded (or blocked) coronary artery have demonstrated lessened mortality.

My first exposures to the field of neurointerventional surgery were through reading reports from Germany. In 1983, Zeumer, Hacke and Ringelstein reported that three of five patients with typically fatal strokes caused by occlusion of the basilar artery improved after streptokinase, an agent known to dissolve blood clots (called thrombolytic agents), was injected by a catheter into the artery-clogging clot. A year later, Zeumer and Ringelstein reported two cases successfully treated by injection of another thrombolytic agent, urokinase, into clots blocking the intracranial carotid arteries. The basilar and carotid arteries are the major routes of blood flow to the brain. Like basilar occlusion, blockage at the top of the carotid artery is often fatal, or otherwise results in lifelong disability. This pioneering work in Germany offered hope that successful treatment for the most severe strokes was possible. In 1989 at the Mass. General Hospital, we instituted an acute stroke service for the intra-arterial treatment of severe strokes. The “miracle” recoveries that were occasionally seen after opening these brain arteries in the “angio” suite infused a high level of enthusiasm.

The field has taken a number of twists and turns over the past 30 years, but with the reports at the stroke conference this February, the procedure of using a catheter to physically penetrate and then dissolve or remove large clots in brain arteries can now be widely considered to be beneficial.

Intravenous (IV) administration into the circulatory system of tissue plasminogen activator (t-PA), also a thrombolytic agent, became standard of care after publication of the NINDS trial in 1995. IV tPA does not penetrate into the clots but instead works at the interface between the clot and the blood stream.  As a result IV t-PA had limited ability to dissolve the large clots that caused the most severe strokes.  In 1999, an Abbot pharmaceuticals-funded, randomized controlled trial injecting pro-urokinase, a novel thrombolytic, via a catheter directly into the center of the clot blocking the major brain arteries showed benefit, but the FDA required a confirmatory study and the company decided not to proceed. Beginning in the mid-1990’s NINDS funded a series of linked studies – Emergency Management of Stroke (EMS) followed by the Interventional Management of Stroke (IMS) trials (IMS, IMS I/II, and IMS III) - to test the ability of intra-arterial therapy to rescue patients with severe strokes despite treatment with IV t-PA. In 2013, disappointment in the field was palpable when IMS III showed no benefit of intra-arterial therapy in addition to the benefit of IV t-PA.

Two major advances that occurred since IMS III was first designed may have led to recent successes. First, the field moved from injecting thrombolytic agents that dissolved clots over time to deploying stents that could capture the clot and remove it from the artery when the device is removed from the vessel. These stent-retrievers are more effective in removing clots and they are easier and faster to deploy than previous devices.  The early EMS and IMS trials used the injection approach, whereas IMS III used the injection approach and also began incorporating the newer approach with clot-retrieval devices as their use began to increase during the course of the trial. The latest trials reported this February utilized the Solitaire stent retrieval device made by Covidien (now Medtronic).

Schematic of how the clot retriever used in the reported trials is opened inside a blood vessel to surround a clot that is blocking blood flow.  Once caught by the stent, the entire apparatus with the clot is removed from the body out a small puncture in the femoral artery at the groin.

The second advance was the use of imaging techniques (see below) to select patients for the study who have both large clots and incomplete brain injury. By injecting a common contrast agent intravenously with the brain CT scan (CT angiography) or MRI (MR angiography), large artery blockages can easily be identified. In addition, CT or MRI techniques can now also define the degree of irreversible injury that is associated with poor outcome even if the vessel is opened, i.e., when it is too late to save brain tissue.

  1. Top row is non contrast CT scan without evidence of infarction yet in a patient with blockage of the middle cerebral artery on the left side of the image. Second and third rows are from a contrast CT scan that shows dilated vessels on the side of the stroke (left side of the image), a “good pattern” indicating collateral flow is keeping the brain alive.
  2. Contrast CT scan, CT angiography or “CTA” demonstrating blockage at arrow of the middle cerebral artery on the left side of the image.
  3. Cather angiogram demonstrating the same blockage prior to an intra-arterial procedure.

In addition, IMS III results suggested there might be harm associated with performing the angiographic procedures under general anesthesia, which the recently reported studies also confirmed.  IMSIII also impressed upon the field that it was crucial to enroll patients into randomized controlled trials, an idea that was not widely held by the community during IMSIII.

After IMS III, NINDS met with various stakeholders to consider next steps for a trial utilizing noninvasive angiography and tissue imaging to select patients for intra-arterial therapy with the newest devices. However, multiple parties were already planning independent studies with support from industry partners. Thus the results of these four latest trials have been highly anticipated by the community, since they build on decades of investment and development in this new approach that had yet to realize its full potential to revolutionize treatment of severe acute strokes

2015 Studies

Study Number of patients Proportion of patients with independent level of function at 90 days Notes

Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands
(MR CLEAN)

NEJM 2015 372: 11-20.

500

Control: 19% (n=267)

Intervention: 33% (n=233)

>87% of the patients received IV t-PA before being randomized to intra-arterial clot retrieval. The angiographic procedure was started in the first 6 hours after stroke onset. The blood vessel was open at 24 hours in 75% of the intra-arterial cases as compared to 32% of the controls. Patients in the intra-arterial arm had a 67% improved functional outcome as compared to the controls. The infarct size was also smaller in the intra-arterial group.

Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE)

NEJM 2015 Feb 11 [Epub ahead of print]

316

Control: 29% (n=150)

Intervention: 53% (n=165)

The study was carried out in Canada, South Korea, the United Kingdom and Ireland. The Data and Safety Monitoring Board (DSMB) stopped the study when an interim analysis showed clinical benefit. Investigators demonstrated great efficiency, taking only 90 minutes to open the artery from the time of the CT scan. 75% of patients received IV t-PA. Mortality also decreased by 40% in the intra-arterial group.

Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial Trial (EXTEND-IA)

NEJM 2015 Feb 11 [Epub ahead of print]

70

Control: 40% (n=35)

Intervention: 71% (n=35)

This study was carried out in Australia and New Zealand, utilizing a perfusion imaging technique that was developed at Stanford University with NINDS funding. Investigators calculated the ratio of the amount of brain tissue that is under-perfused to the amount already dead and selected patients where the ratio was>1.2. They excluded those in which imaging demonstrated that extensive tissue damage had already occurred. All patients received IV t-PA. The DSMB halted this study after 70 patients were entered out of a planned 100.

SolitareTM FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME)

196+

Control: 36%

Intervention: 60%

This study includes 25 US sites and 19 international sites with planned interim analysis when the first 200 patients are enrolled. Like the other studies, these investigators utilized CT or MR angiography to identify the large artery blockage and exclude patients with evidence of extensive damage on the CT or MRI scan. All patients received IV t-PA.

In addition to these reports, another trial in Spain was stopped by the DSMB, but final results were not available at the time of the International Stroke Conference.

NINDS congratulates these investigators and expresses deep appreciation to the patients who enrolled in these studies. These findings demonstrate the ability of rapid recanalization of blocked brain blood vessels to save many acute stroke patients from severe, usually lifelong, disability or death. Systems of care are in place to rapidly identify appropriate stroke patients for this treatment and get them to the neuro-angiographic suite for the procedure. However, efficient processes will need to be implemented in more stroke centers across the country to ensure quality and minimize harm as use of this approach becomes more widespread. In addition, recording the time to recanalization in such patients will greatly aid researchers in developing novel means to slow down the time course of brain damage. The goal remains to deliver therapies with greater benefits to more patients, and this breakthrough is an important step in that direction.

See More on the NIH Director’s Blog:  http://directorsblog.nih.gov/2015/03/10/clot-removal-impressive-results-for-stent-retrievers-in-acute-stroke/

References:

  1. Zeumer H, Hacke W, Ringelstein EB. Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. AJNR Am J Neuroradiol 1983 May-Jun; 4(3): 401-4.
  2. Zeumer H, Hündgen R, Ferbert A, Ringelstein EB. Local intraarterial fibrinolytic therapy in inaccessible internal carotid occlusion. Neuroradiology. 1984; 26(4): 315-7.
  3. Furlan A1, 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; 282: 2003-11.
  4. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec 14; 333(24): 1581-7.
  5. Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1; 372(1): 11-20.
  6. Goyal M et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015 Feb 11 [Epub ahead of print].
  7. Campbell BC et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015 Feb 11 [Epub ahead of print].
  8. Hunter GL et al. Assessment of cerebral perfusion and arterial anatomy in hyperacute stroke with three-dimensional functional CT: early clinical results. AJNR Am J Neuroradiol 1998 Jan: 19(1): 29-37.
Friday, February 20, 2015