Authors: Wesley George, MD (EM Resident Physician, Rutgers NJMS) and Miriam Kulkarni, MD (EM Attending Physician, Assistant Program Director, Rutgers NJMS) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)

At a Crossroads

Every few years, we come to a crossroads that makes us reexamine our current clinical practice and consider a better intervention. For the past twenty years, patients presenting with acute ischemic stroke have had essentially one option for therapy: intravenous thrombolytics. Since the NINDS-2 trial in 1995 [1], tPA has erupted onto the scene of stroke management and has become the gold standard despite ongoing questions behind the true efficacy of tPA.

Endovascular intervention has been present since the early 2000s. There are two main types: intraarterial tPA and mechanical thrombectomies to remove clots that are occluding brain vessels. However, most of these therapies failed to show benefit, and more importantly had increased risks with the intervention. The first of these studies is the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) in 2005 and 2008 [2,3] that showed high rates of complications including arterial perforations. Even as recently as 2013, multiple trials including Intra-arterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS), Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Interventional Management of Stroke (IMS-III) [4,5,6] all failed to show true benefit of endovascular repair.

Defining Studies

Things drastically changed at the end of 2014 when one of the first major positive trials for endovascular therapy emerged – the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) [7]. This study was the harbinger of a new era in endovascular repair. MR CLEAN is a multicenter randomized clinical trial that compared patients receiving either standard care (IV tPA) vs. standard care with additional endovascular therapy (ET). Five hundred patients at 16 centers in the Netherlands who presented with acute ischemic stroke and anterior proximal artery occlusion identified by angiographic imaging within 6 hours after stroke onset were enrolled. The results showed an improved neurological outcome at 90 days with a 13.5% absolute increase in patients with functional independence at 90 days and an NNT of 7. These results were so successful, that the trial was stopped early due to benefit.

Immediately following the MR CLEAN trial, two similarly designed validating studies were also published in the New England Journal of Medicine – the Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial (EXTEND-IA) trial and the Endovascular Treatment for Small Core and Anterior Circulation Proximal occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trials [8,9]. Once again, both trials showed promise. In the EXTEND-IA trial, which used CT perfusion imaging to identify patients who had evidence of salvageable brain penumbra showed improved neurological improvement at 3 and 90 days with a 31% absolute increase in neurological functional independence favoring the ET group compared to the usual care group. The ESCAPE trial also showed benefits in the ET group with a 33.7% absolute increase in functional independence. Even more exciting was that for the first time ever in any endovascular therapy study in history, there was a mortality benefit at 90 days of 8.6% in the ET group. Both the EXTEND-IA and ESCAPE trial were once again halted due to overwhelming benefit.

Most recently, two more trials that were both sponsored by the retrievable stent maker (Covidien) also showed similar results to the preceding ET studies. The Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke (SWIFT PRIME) and the Thrombectomy within 8 hours after Symptom Onset in Ischemic Stroke (REVASCAT) trials once again showed benefit [10,11]. The SWIFT-PRIME results showed an absolute difference of 25% in the patients that were functionally independent favoring the ET group and an NNT of 4 to have one patient alive and independent at 90 days. The REVASCAT study also showed higher rates of 90 day functional independence in the ET group with an absolute risk reduction of 16%.

Repeating History?

One would think that with these results, we should be jumping to implement endovascular repair throughout the country. However, we may have to look at our past to understand the limitations. These series of ET studies may be a repeat of how tPA was prematurely pushed as the standard of care for ischemic stroke.

The publication of the NINDS-2 trial in 1995 ushered in a new age of stroke management that allowed more intensive management of ischemic stroke [1]. Prior to the NINDS-2 trial, previous trials that included the NINDS-1, MAST-1, and ECASS trials all showed an increase in mortality in patients who received tPA [1,12,13]. Even years after the introduction of tPA, multiple studies have failed to show benefit, and some even showed harmful outcomes of tPA administration [14,15,16,17,18]. The NINDS-2 trial showed promising results including a 13% absolute increase in patients who were alive and independent at 90 days in the tPA arm[1]. However, at least 13 other trials since the introduction of tPA have failed to replicate these results. The FDA and pharmaceutical interests ignored multiple studies that showed no benefit and even harm, but fast tracked tPA into the market and ultimately made it the standard of care for ischemic stroke to this day.

In the same way, multiple studies since the early 2000s have showed no benefit and even harm for endovascular therapy, but the pro-ET community has started to push this therapy since the introduction of the MR CLEAN trial. Why have these newer studies showed benefit when multiple prior studies have showed none? While each of the studies have its’ own strengths and limitations in showing the true efficacy of endovascular therapy, the primary message that reverberates throughout all of the studies is that there is a limited population that will actually benefit from the therapy. All of the trials focused on patients with severe strokes with large vessel occlusions and salvageable brain tissue. However, that population is a fraction of the stroke patients that arrive in the emergency room. EXTEND-IA recruited only 0.3 patients per center per month and ESCAPE did not fare much better with 1.44. In the SWIFT-PRIME trial, it took nearly 2 years in 39 different centers to enroll 196 patients. For a carefully selected population of patients, endovascular repair can dramatically improve neurological outcome and decrease mortality. The challenge of the future will be identifying and delivering this therapy to the patients who can benefit from it.

A Promising Future

At the International Stroke Conference in February 2015 in the midst of the publication of these studies, multiple neurointerventionalists and neurologists hailed the studies as a “new day in stroke management”. This may be true, but excitement for the results of these studies should be taken with caution and cannot be a blanket therapy for all stroke patients. During the conference, the principal investigator of SWIFT-PRIME, Dr. Jeffrey Saver, mentioned that an estimated 60,000 stroke patients per year are eligible for endovascular therapy in just the United States. However to achieve this, 300 comprehensive stroke centers would have to be established in the US, but only about 75 are established in the country at this time. It will take time and large-scale planning and investment to achieve the task of implementing these changes.

The American Heart Association/American Stroke Association placed their stamp of approval on endovascular treatment by publishing new ischemic stroke guidelines in June 2015[19]. They stated that certain ET procedures have shown clinical benefit in selected patients with acute ischemic stroke and healthcare systems should be organized to facilitate the delivery of this care. This may be the strongest push for implementing endovascular therapy as the standard care.

While the road ahead looks promising, clinicians should understand that the initial findings of ET in the selected population should be reserved for just that – selected populations. Instead of casting a wide net for ET for all stroke patients, we should comb through the multitude of stroke patients to find that unique population that will ultimately benefit from endovascular therapy.

References / Further Reading

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;333(24):1581-7. Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1177-82. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008 Apr;39(4):1205-12. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):904-13. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):914-23 Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke (MR CLEAN). N Engl J Med. 2015;372:(1)11-20. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection (EXTEND-IA). N Engl J Med. 2015;372:1009-18. Goyal M, Demchuk AM, Menon BK, et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke (ESCAPE). N Engl J Med. 372:1019-30 Saver JL, Goyal M, Bonafe A, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. (SWIFT PRIME) N Engl J Med. 2015 Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. (REVASCAT) N Engl J Med. 2015; Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-14. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-25. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group. N Engl J Med. 1996;335(3):145-50. ​Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-6. ​Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-51. ​Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282(21):2019-26. ​Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study: Thrombolytic Therapy in Acute Ischemic Stroke Study investigators. Stroke. 2000; 31: 811–816. Powers W, Derdeyn C, Biller J, et al. 2015 AHA/ASA 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; published online before print June 29 2015 http://www.ncbi.nlm.nih.gov/pubmed/25441245