Intravenous Thrombolytic Therapy Remains the Basis and Mainstay of Revascularizing Therapy!

Peter D. Schellinger, MD; Martin Köhrmann, MD


Stroke. 2018;49(10):2285-2286. 

" Have you ever had a dream, Neo, that you were so sure was real? What if you were unable to wake from that dream? How would you know the difference between the dream world and the real world?"
—Morpheus, from the movie The Matrix, 1999
" Facts are stubborn things; and whatever may be our wishes, our inclinations, or the dictates of our passion, they cannot alter the state of facts and evidence."
—Summation of John Adams, Pleading in the Boston Massacre Trial, October 24–30 1770, The Legal Papers of John Adams, No. 64, Rex v Wemms

Ongoing discussions address the benefit, lack thereof, or even harm of intravenous treatment with alteplase (IVT) before performing endovascular therapy (EVT) of acute stroke. Although there is no doubt, that EVT within 6 to 8 hours from symptom onset in patients with large vessel occlusion is a highly effective treatment (as it is up to 24 hours in highly selected patients),[1,2] it is a fact that in the early time window, ≈90% of patients received IVT before going on to EVT. At the current time point, according to all available evidence, colleagues, who progress to EVT without IVT in patients where there are no contraindications and only indications for IVT, may live in a dream world and ignore facts and solid evidence.

No theoretical argument, such as resistance of a given clot because of proximality, clot consistence, promotion of blood brain barrier damage, vessel damage and ultimately bleeding, clot fragmentation, prolongation of time to EVT, or any other argument lacking randomized controlled clinical trial data, has been backed by good observational evidence, at least the perceptions are contradictory.[3] Recent larger observational series and meta-analyses speak in favor of the combined IVT/EVT approach showing better functional outcomes, lower mortality, and higher rates of recanalization without increased intracranial hemorrhage rates.[4–6] Granted, these analyses all have in common, that they were not randomized for this question always leading to a comparison of a good prognosis with a notoriously poor prognosis set of patients. In addition, from a medicolegal perspective, it seems safer to apply rather than to withhold IVT, when indicated, as law suits for IVT not being given account for the vast majority of acute stroke therapy–related malpractice claims (as opposed to, eg, bleeding complications).[7] For drip and ship patients, the question of withholding accordingly does not apply. A case in point is that in drip and ship patients (currently a large portion if not the majority of EVT patients), a relevant number of patients arriving at the comprehensive stroke center (aka, mothership) have experienced recanalization of the proximal clot, especially in M1 and M2 segment occlusions.[8] The number of recanalized drip and ship patients with initial occlusion cannot be established from the randomized trials as screening logs notoriously fail to register these patients. However, two-thirds of patients in the interventional management of stroke 3 study[9] with computed tomography angiography-based assessment and M1 occlusions achieved recanalization by IVT alone favorable outcome rates being excellent. In personal communications, aborted or unnecessary EVT procedures on dripped-and-shipped patients because of recanalization or clearly demarcated or extensive signs of infarction on follow-up imaging are reported with rates ≈50%.

In accordance with the discussion above, secondary findings from the ASTER (Effect of Endovascular Contact Aspiration vs Stent Retriever on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion) Randomized Clinical Trial[10] published in this issue of the journal[11] corroborate the use of IVT before EVT. ASTER compared contact aspiration versus stent retriever technique for EVT randomizing a total of 381 patients failing to show any differences between both techniques in terms of recanalization rates and clinical outcomes.[10] In this post hoc analysis (primary outcome modified Rankin Scale score ≤2), the authors present the results for patients receiving IVT and EVT (n=250) versus EVT alone (n=131). There were no significant differences in outcomes, bleedings, or reperfusion rates between the 2 groups, with the exception of a reduced mortality rate that was documented in patients receiving combination therapy.[11] Patients without previous anticoagulant therapy showed better outcomes and recanalization rates needing less device passes when undergoing EVT. The problem (acknowledged by the authors) with this analysis as with others is that patients not receiving IVT represent a poor prognosis group per se because of risk factors, surgery, concomitant medication, time window, infarct size, or other reasons. Therefore, although the results of the ASTER subgroup analysis are interesting, unfortunately they do not answer the relevant question, we need to answer. Do we need IVT before EVT? Is it beneficial, is it more dangerous but still beneficial, is it beneficial in a subgroup of patients (such as those without previous anticoagulation), is it just not adding anything in terms of safety and efficacy and could therefore be abandoned just for cost reasons, etc? We have 2 effective therapies, does it make sense to not use either one when we do not even know that we can use the other one?

Facts are facts, dreams are dreams, and aspirations are aspirations. As a consequence, drip and ship patients must be pretreated with IVT when indicated. If at all, a mothership trial, randomizing patients to IVT/EVT versus direct EVT may shed further light on the additional effect of IVT—whether it be good, bad, or neutral—in stroke patients with large vessel occlusion. Screening logs should assess in how many patients IVT was withheld and EVT was technically not possible so that the patient did not get any treatment at all. These trials are underway, but their results should be carefully communicated clarifying that they only apply to mothership patients irrespective of what the results actually are. Until their results become available, IVT remains the standard of care outside a clinical trial in patients where according to national and international guidelines IVT is indicated.

" My business is to teach my aspirations to conform themselves to fact, not to try and make facts harmonise with my aspirations"
—Thomas Henry Huxley (1825–1895), from a letter to Charles Kingsley, September 23, 1860"