Debate: IV thrombolysis in acute stroke treatment is dead

It has now been universally accepted that mechincal thrombectomy for the treatment of patients with acute ischaemic stroke with large vessel occlusions is the future. But what does that mean for long-time gold standard treatment of intravenous (IV) thrombolysis? In this Brain to Brain debate, Keith W Muir and Urs Fischer weigh in on whether stroke patients should still be receiving IV thrombolysis at all.

Is IV thrombolysis dead? Far from it

By Keith W Muir

Endovascular mechanical thrombectomy is an important advance for those patients with large artery occlusive, anterior circulation stroke, but all that we know about this treatment modality is built on a foundation of highly efficient provision of intravenous thrombolysis—this applies equally to the 90% of participants in recent endovascular trials who had received IV thrombolytic drugs as part of standard care, but also to the 10% of trial participants who were considered ineligible for IV thrombolysis, since these patients benefitted from the same streamlined assessment process for selection. Median stroke onset to start of IV thrombolysis times in the recent trials were superior to all previously published data on routine thrombolytic treatment (as short as 85 minutes in the MR CLEAN trial,¹ and overall median 100 minutes across all five published trials²).

In order to justify omission of an established and effective treatment—IV thrombolysis—very robust evidence should be demanded. This presently is not available.
While individual patient data meta-analysis of the five trials included in the HERMES collaboration, including the 188 patients deemed ineligible for IV thrombolysis, yields a point estimate for effect very similar to those who received IV alteplase, the small sample means that confidence intervals are wide and encompass the possibility that the true effect may differ.² Randomised trial data that are now unfashionable—the SYNTHESIS expansion trial³—indicate that bypassing the established IV thrombolysis pathway in favour of a “more effective” endovascular approach may not be in the patient’s interest: outcomes of endovascular treatment in SYNTHESIS were not different compared to IV thrombolysis alone, and a probable reason for this lies in the additional delay incurred in starting endovascular procedures. Devices and team organisation have improved since SYNTHESIS but “better” recanalisation may yet fail if it is not also “faster”.

Contrary to a frequently repeated claim that “IV thrombolysis does not work” for some categories of patient, recent trials report higher rates of recanalisation with IV therapy alone, even for large vessel and high clot burdens,⁴ than were documented in older studies. In EXTEND-IA, 11% of eligible patients had already largely recanalised prior to angiography.⁵ The same proportion in SWIFT PRIME either could not have endovascular treatment (because of vascular access issues or imaging misinterpretation) or no longer needed it because recanalisation had occurred.⁶ Intention to treat with endovascular approaches neither guarantees that this is feasible, or necessary. The rapidly declining benefit of IV thrombolysis over the first hours⁷ does not concur with the time scale for loss of viable tissue on imaging,⁸ and therefore may reflect modification of clot characteristics that make successful lysis less likely. Earlier delivery of IV therapy alters the landscape for IV therapy as well as for endovascular treatment, and it is wrong to assume that figures from studies conducted many years ago reflect today’s reality as door to needle times shorten.

IV therapy itself does not stand still, but continues to evolve. Data already indicate both safety and efficacy of IV alteplase in many of the patient groups excluded from clinical trials and thus the current alteplase licence.^9,10 When faced with a patient who falls out of the licence criteria, the first question that a clinician ought to consider is whether the totality of evidence truly indicates a different risk:benefit balance in that individual compared with those who fall within licence. In a great many cases there is no evidence of greater risk or lower benefit, and IV thrombolysis should be considered. Trials investigating alternative doses of alteplase, alternative thrombolytic agents, and combination therapies, all promise to alter the landscape for IV therapy in the near future, with the prospect of safer and more effective IV therapy.¹¹

Finally, and perhaps most importantly, endovascular treatment is currently inappropriate, inaccessible or unavailable for most stroke patients even in those high-income countries where pockets of expertise exist—worldwide it represents a tiny fraction of activity. IV thrombolysis can, in contrast, be delivered to a significant proportion of patients, and can even be brought to geographically remote areas with telemedicine.

In conclusion, IV thrombolysis is an effective treatment that should be initiated in all eligible patients as rapidly as possible, irrespective of whether subsequent eligibility for additional endovascular treatment is determined. Endovascular treatment in IV thrombolysis-ineligible patients appears to be a reasonable option based on a very limited amount of data, but grounds for ineligibility need to be considered carefully, and future evolution of IV thrombolytic treatments may well modify the risk:benefit balance. Is IV thrombolysis dead? Far from it: it is the basis for providing endovascular care for the small proportion of patients who require it, and ongoing trials are likely to reinvigorate it.

References

1. Berkhemer OA, Fransen PS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. The New England Journal of Medicine 2015; 372(1): 11–20.
   2. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016.
   3. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. The New England Journal of Medicine 2013; 368(10): 904–13.
   4. Demchuk AM, Goyal M, Yeatts SD, et al. Recanalization and clinical outcome of occlusion sites at baseline CT angiography in the Interventional Management of Stroke III trial. Radiology 2014; 273(1): 202–10.
   5. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. The New England Journal of Medicine 2015; 372(11): 1009–18.
   6. Saver JL, Goyal M, Bonafe A, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. The New England Journal of Medicine 2015.
   7. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; 384(9958): 1929–35.
   8. Cheripelli BK, Huang X, McVerry F, Muir KW. What is the relationship among penumbra volume, collaterals, and time since onset in the first 6 h after acute ischemic stroke? International Journal of Stroke 2016; 11(3): 338–46.
   9. Meretoja A, Putaala J, Tatlisumak T, et al. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke 2010; 41(7): 1450–8.
   10. Frank B, Grotta JC, Alexandrov AV, et al. Thrombolysis in stroke despite contraindications or warnings? Stroke 2013; 44(3): 727–33.
   11. Ramani L, Huang X, Cheripelli B, Muir KW. Intravenous thrombolysis for acute stroke: current standards and future directions. Current Treatment Options in Cardiovascular Medicine 2015; 17(4): 373.

Keith W Muir is SINAPSE professor of Clinical Imaging & consultant neurologist at the Institute of Neuroscience & Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK

Acute endovascular stroke treatment: “To bridge or not to bridge, that is the question!”

• IV treatment before mechanical thrombectomy is of no benefit

By Urs Fischer

The unanswered question
In 1996 the US Food and Drug Administration approved intravenous thrombolysis with recombinant tissue plasminogen activator (IV rt-PA) for treatment of acute ischaemic stroke based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) trial.¹ In the meantime, IV rt-PA has become the “holy grail” of acute stroke treatment and is currently the standard treatment of care for all eligible stroke patients presenting within 4.5 hours after symptom onset.

However, the field of intravenous thrombolysis has been stagnant for the last 20 years. The major breakthrough in modern stroke treatment came in 2015, when five randomised controlled trials consistently showed that endovascular clot retrieval in addition to best medical treatment (± IV rt-PA) improves outcome in acute anterior circulation stroke patients with proximal vessel occlusion.^2,3,4,5,6 Interestingly enough, a meta-analysis of individual patient data from these five randomised trials did not show any difference in outcome in patients who received alteplase and those who were ineligible for IV rt-PA.
Whether treatment with IV rt-PA prior to mechanical thrombectomy is of any benefit has currently become an important unanswered question in acute stroke treatment.

Pros and cons of bridging therapy
There are several arguments for and against administering IV rt-PA in acute stroke patients with a proximal vessel occlusion in the anterior circulation:

• IV rt-PA can be started earlier than mechanical thrombectomy and may produce recanalisation and reperfusion, avoiding the need for embolectomy.⁹ However, in the recent landmark trials, reperfusion prior to embolectomy occurred in only 5–10% of patients. Reperfusion rates depend on the site of vessel occlusion with very low rates in internal carotid artery (ICA) occlusions and with higher rates in occlusions in the M2 segment of the middle cerebral artery (MCA).
• IV rt-PA may facilitate embolectomy and may result in fewer stent retriever passes.⁹
• IV rt-PA may help to recanalise thrombi in small vessels and in the microvascular structure, inaccessible for endovascular devices.⁸

On the other hand, rt-PA has several important limitations:⁹

• IV rt-PA may increase the risk of intracerebral haemorrhage (ICH) and any other bleeding complications.⁸ Kidwell et al found that intravenous or intra-arterial rt-PA resulted in a greater breakdown of the blood-brain barrier compared with embolectomy or no treatment.
• IV rt-PA is ineffective in the majority of patients with large thrombi and in patients with large vessel occlusions.
• IV rt-PA may result in migration of thrombi from proximal into distal vessels, where thrombectomy is no longer possible.
• Immediate administration of antiplatelet agents and heparin are contraindicated for 24 hours after IV rt-PA, but potentially beneficial after endovascular intervention and clearly indicated when stents have to be placed during the endovascular procedure.⁸
• The therapeutic window for IV rt-PA is narrow with a rapidly increasing number needed to treat.⁸
• IV rt-PA has a considerable impact on healthcare costs: IV rt-PA, which is eventually not beneficial in these patients would unnecessarily increase the cost of treatment in patients presenting with proximal vessel occlusion, if stent retriever thrombectomy alone is equally effective as IV rt-PA followed by stent retriever thrombectomy.⁹
• Many patients with severe strokes and large vessel occlusions have absolute or relative contraindications for IV rt-PA (ie. wake-up strokes, borderline coagulation status, high blood pressure and glucose levels, etc.) putting them at an increased risk of ICH.⁸
• IV rt-PA prior to endovascular clot retrieval might even delay endovascular therapy, especially in centres where patients can be quickly moved to the endovascular suite.
• Initial triage to a primary stroke centre for administration of IV rtPA may delay transfer to a comprehensive stroke centre for embolectomy.⁹
• IV rt-PA causes some rare side effects such as life-threatening orolingual angioedema.⁸

Current evidence
Several studies compared IV rt-PA eligible patients treated with mechanical thrombectomy with IV rt-PA ineligible patients: The proportion of functionally independent patients at 90 days were similar across studies ranging 48–68% in the IV rt-PA plus mechanical thrombectomy group and 42–59% in the mechanical thrombectomy alone group.^12,13,14,15 These data were confirmed in the above-mentioned meta-analysis of individual patient data from the five randomised trials.⁷ However, in all these studies patients treated with mechanical thrombectomy alone had contraindications for IV rt-PA, which makes a direct comparison of these different patient groups difficult.

Only recently, two studies compared clinical and radiological outcomes of patients treated with IV rt-PA in combination with mechanical thrombectomy to IV rt-PA eligible patients treated with mechanical thrombectomy alone directly referred to comprehensive stroke centres.^8,16 In both studies, outcome in patients treated with bridging thrombolysis and those with mechanical thrombectomy alone did not differ, but rates of haemorrhages tended to be higher in bridging patients than in those, treated with mechanical thrombectomy alone.

Relevance
Critics argue that the proportion of patients treated with endovascular treatment is only relevant for a small minority of patients in advanced healthcare systems, and therefore the question whether patients should be treated with IV rt-PA is irrelevant.¹⁷ However, recent positive trials have boosted the proportion of patients treated with thrombectomies in many countries. In well-established comprehensive stroke centres with a large network of stroke units, up to 20% of stroke patients referred to a comprehensive stroke centre are currently treated with mechanical thrombectomy (unpublished data from the Bernese stroke registry).

Outlook
IV rt-PA will remain the standard of care for all patients presenting within 4.5 hours after symptom onset with peripheral vessel occlusion. However, current evidence suggests that direct mechanical intervention may be equally effective compared to bridging thrombolysis in patients with large anterior circulation stroke and there is equipoise that calls for a randomised trial. A randomised trial comparing mechanical thrombectomy alone with bridging therapy in patients directly referred to a comprehensive stroke centre, where immediate reperfusion is possible could solve this question and is currently planned.

Therefore, one of the relevant unanswered questions in acute stroke treatment 400 years after the death of William Shakespeare is: “To bridge or not to bridge. That is the question!”

Acknowledgments
Prof. Dr. Jeffrey L. Saver, UCLA Comprehensive Stroke Center, Los Angeles, USA
Prof. Vitor Mendes Pereira, Department of Surgery Toronto Western Hospital, Toronto, Canada
Prof. Jan Gralla, Department of Diagnostic and Interventional Neuroradiology, Bern, Switzerland

References

1. 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.
2. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20.
3. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. N Engl J Med. 2015;372:2285–95.
4. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–30.
5. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–18.
6. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. N Engl J Med. 2015;372:2296–306.
7. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Dávalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millán M, Davis SM, Roy D, Thornton J, Román LS, Ribó M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG; HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016 Feb 18. pii: S0140-6736(16)00163-X
8. Broeg-Morvay A, Mordasini P, Bernasconi C, Bühlmann M, Pult F, Arnold M, Schroth G, Jung S, Mattle HP, Gralla J, Fischer U. Direct Mechanical Intervention Versus Combined Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. Stroke. 2016 Apr;47(4):1037–44
9. Chandra RV, Leslie-Mazwi TM, Mehta BP, et al. Does the use of IV tPA in the current era of rapid and predictable recanalization by mechanical embolectomy represent good value? J. Neurointerv. Surg. Jan 12 2016.
10. Kidwell CS, Latour L, Saver JL, et al. Thrombolytic toxicity: blood brain barrier disruption in human ischemic stroke. Cerebrovasc Dis 2008;25:338–43.
11. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke. 2011;42:1775–7.
12. Davalos A, Pereira VM, Chapot R, et al. Retrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke. Stroke. Oct 2012;43(10):2699–2705.
13. Pereira VM, Gralla J, Davalos A, et al. Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke. Stroke. Oct 2013;44(10):2802–7.
14. Leker RR, Pikis S, Gomori JM, Cohen JE. Is Bridging Necessary? A Pilot Study of Bridging versus Primary Stentriever-Based Endovascular Reperfusion in Large Anterior Circulation Strokes. J. Stroke Cerebrovasc. Dis. Jun 2015;24(6):1163–7.
15. Guedin P, Larcher A, Decroix JP, et al. Prior IV Thrombolysis Facilitates Mechanical Thrombectomy in Acute Ischemic Stroke. J. Stroke Cerebrovasc. Dis. May 2015;24(5):952–7.
16. Weber R, Nordmeyer H, Hadisurya J, et al. Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis. J. Neurointerv. Surg. Feb 22 2016.
17. Muir K. No space left for intravenous thrombolysis in acute stroke: CONS. Intern Emerg Med. 2016 Apr 15

Urs Fischer is professor for Acute Neurology and Stroke and co-director of the Clinical Trial Unit at the University of Bern, Switzerland