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EJMINT Editorial, 2013: 1335000120 (29th August 2013)

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The ESMINT and ESNR statement regarding trials evaluating the endovascular treatment at the acute stage of ischemic stroke
Laurent Pierot, Michael Söderman, Martin Bendszus, et al
EJMINT Editorial, 2013: 1335000120 (29th August 2013)

The ESMINT and ESNR statement regarding trials evaluating the endovascular treatment at the acute stage of ischemic stroke

EJMINT Editorial, 2013: 1335000120 (29th August 2013)
Laurent Pierot, Michael Söderman, Martin Bendszus, Philip M White, Mario Muto, Francis Turjman, Salvatore Mangiafico, Jan Gralla, Jens Fiehler, István Szikora, Christophe Cognard

Abbreviations

EVT
endovascular treatment
AIS
acute ischemic stroke
ESMINT
European Society of Minimally Invasive Neurological Therapies
ESNR
European Society of Neuroradiology
IA
intra-arterial
RCTs
randomised clinical trials


The recent, simultaneous publications of the neutral results of three randomised studies (Synthesis, IMS III, and MR-Rescue) comparing IV thrombolysis therapy to the endovascular treatment (EVT) of acute ischemic stroke (AIS) has been followed by several editorials pointing out their limitations and drawbacks [1-6]1. Broderick JP, Palesch YY, Demchuk AM, et al.; Endovascular treatment after intravenous rTPA versus rTPA alone for stroke; N Engl J Med 2013; 368: 893-903.2. Ciccone A, Valvassori L, Nichelatti M, et al.; Endovascular treatment for acute ischemic stroke; N Engl J Med 2013; 368: 904-913. [PubMed] [Full Text Sources]3. Kidwell CS, Jahan R, Gornbein J, et al.; A trial of imaging selection and endovascular treatment for ischemic stroke; N Engl J Med 2013; 368: 914-923. [PubMed] [Full Text Sources]4. Von Kummer R, Gerber J. IMS III; Synthesis, and MR Rescue: no disaster, but down to earth; Clin Neuroradiol 2013; 23: 1-3.5. Meschia JF, Barrett KM, Brott TG; Reperfusion therapy for acute ischemic stroke: How should we react to the third Interventional Management of Stroke trial? Mayo Clin Proc 2013; 88: 653-657. [PubMed] [Full Text Sources]6. Pierot L, Gralla J, Cognard C, White P; Mechanical thrombectomy after IMS III, Synthesis, and MR Rescue; AJNR Am J Neuroradiol 2013; Jun 6 (Epud ahed of print).. The two European Societies dealing with Interventional Neuroradiology (ESMINT and ESNR) have, in a working group dedicated to acute stroke treatment, analysed the results of these studies leading to the recent publication: “Statement of ESMINT and ESNR regarding trials evaluating the endovascular treatment at the acute stage of ischemic stroke” in Neuroradiology [7]7. Pierot L, Söderman M, Bendszus M, White P, Muto M, Turjman F, Mangiafico S, Gralla J, Fiehler J, Szikora I, Cognard C; Statement of ESMINT and ESNR regarding recent trials evaluating the endovascular treatment at the acute stage of ischemic stroke; Neuroradiology. 2013; DOI 10.1007/s00234-013-1249-3 (in press).. The same group has already published documents regarding the definition of rules regarding trials evaluating the EVT of AIS [8-9]8. Fiehler J, Söderman M, Turjman F, et al.; Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR. Part I: Current situation and major research questions; Neuroradiology 2012;54:1293-301. [PubMed] [Full Text Sources]9. Fiehler J, Söderman M, Turjman F, et al.; Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR. Part II: Methodology of the future trials; Neuroradiology 2012;54:1293-301..

Medical treatment as well as EVT of AIS has very rapidly evolved over the last 20 years.  If no drugs to date have demonstrated any efficacy in the protection of ischemic brain, the efficacy of IV thrombolysis (with rTPA) was, after several negative randomized clinical trials (RCTs), initially demonstrated in the first 3 h after stroke with later extension of the therapeutic window to 4.5 h [10-19]10. Sutherland BA, Minnerup J, Balami JS, et al.; Neuroprotection for ischaemic stroke: translation from the bench to the bedside; Int J Stroke 2012 ; 7 : 407-418.11. Hacke W, Kaste M, Fieschi C, et al.; Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Stroke Study (ECASS); JAMA 1995; 274: 1017-1025. [PubMed] [Full Text Sources]12. Multicenter Acute Stroke Trial –Italy (MAST-I) Group; Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke; Lancet 1995; 346: 1509-1514. [PubMed]13. The National Institute of Neurological Disorders and Stroke rrTPA Stroke Study Group; Tissue plasminogen activator for acute ischemic stroke; N Engl J Med 1995; 333: 1581-1587.14. The Multicenter Acute Stroke Trial – Europ Study Group; Thrombolytic therapy with streptokinase in acute ischemic stroke; N Engl J Med 1996; 335: 145-150.15. Hacke W, Kaste M, Fieschi C, et al.; Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II); Lancet 1998; 352: 1245-1251. [PubMed] [Full Text Sources]16. Clark WM, Albers GW, Madden KP, et al.; The rtPA (Alteplase) 0- to 6-Hour Acute Stroke Trial, Part A (A0276g): Results of a double-blind, placebo-controlled, multicenter study; Stroke 2000; 31: 811-816.17. Clark WM, Wissman S, Albers GW, et al.; Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study – a randomized controlled trial; JAMA 1999; 282: 2019-2026. [PubMed] [Full Text Sources]18. Hacke W, Kaste M, Bluhmki E, et al.; Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke; N Engl J Med 2008; 359: 1317-1329. [PubMed] [Full Text Sources]19. Wahlgreen N, Ahmed N, Davalos A, et al.; Thrombolysis with alteplase 3-4.5 h after ischaemic stroke (SITS-ISTR) an observational study; Lancet 2008; 372: 1303-1309.. The EVT of AIS has rapidly evolved from intra-arterial (IA) chemical thrombolysis to mechanical thrombectomy [20-30]20. Del Zoppo GJ, Higashida RT, Furlan AJ, et al.; PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke; Stroke 1998; 29: 4-11. [PubMed] [Full Text Sources]21. Furlan A, Higashida R, Wechsler L, et al.; Intraarterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial; JAMA 1999; 282: 2003-2011.22. The IMS study investigators; Combined Intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study; Stroke 2004; 35: 904-912.23. The IMS II trial investigators; The Interventional Management of Stroke (IMS) II trial; Stroke 2007; 38: 2127-2135.24. Ogawa A, Mori E, Minematsu K, et al.; Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke. The Middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan; Stroke 2007; 38: 2633-2639. [PubMed] [Full Text Sources]25. Smith WS, Sung G, Starkman S, et al.; Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial; Stroke 2005; 36: 1432-1438. [PubMed] [Full Text Sources]26. Smith WS, Sung G, Saver J, et al.; Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial; Stroke 2008; 39: 1205-1212. [PubMed] [Full Text Sources]27. Penumbra pivotal stroke trial investigators; The Penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease; Stroke 2009; 40: 2761-2768.28. Castano C, Dorado L, Guerrero C, et al.; Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation. A pilot study; Stroke 2010; 41: 1836-1840. [PubMed] [Full Text Sources]29. Costalat V, Machi P, Lobotesis K, et al.; Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the Solitaire device: a prospective 50-patient single–center study; Stroke 2011; 42: 1929-1935. [PubMed] [Full Text Sources]30. Soize S, Kadziolka K, Estrade L, et al.; Mechanical Thrombectomy in Acute Stroke: Prospective Pilot Trial of the Solitaire FR Device while Under Conscious Sedation; AJNR Am J Neuroradiol 2013; 34: 360-365. [PubMed] [Full Text Sources].

Mechanical thrombectomy was initially performed with no specific tools (injection of saline within the clot, disruption of the clot with a microguidewire, “angioplasty” of the clot with remodeling balloons), then with first-generation devices, such as the Merci and Penumbra devices, developed to catch or aspirate the clot, and finally with second-generation devices (e.g. “stentrievers” such as Solitaire™) developed to promptly restore blood flow through retrieval of the clot. The clinical impact of the use of these novel devices has been impressively illustrated by the recent SWIFT and TREVO 2 trials comparing first-generation and second-generation devices and showing a higher efficacy of second-generation in terms of both recanalisation and crucially clinical outcome [31-32]31. Saver JL, Jahan R, Levy EI, at al.; Solitaire flow restoration device versus Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomized, parallel-group, non-inferiority trial; Lancet 2012; 380: 1241-1249.32. Nogueira RG, Lutsep HL, Gupta R, et al.; Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomized trial; Lancet 2012; 380: 1231-1240..

IMS III, Synthesis, and MR RESCUE are the first RCTs comparing EVT and IV thrombolysis of AIS. They illustrate the difficulties in designing studies for techniques that are in rapid evolution and have important weaknesses. The endovascular techniques used in these trials are varied with most of them now being well recognised to be obsolete. This is related to the relatively long period of inclusion in these trials with the appearance of more efficacious devices during the inclusion period. The length of the inclusion period is primarily due to the small number of patients included per centre per year (2 patients/centre/year in IMS III and 3.5 patients/centre/year in Synthesis) along with a related lack of expertise (this expertise can only be acquired from routine practice of EVT for stroke). The low number of patients/year/centre in the 3 trials probably indicates that all candidates for an IA treatment were not included in the trials and some of them may have been subjected to EVT outside the trial (compassionate use). Such an inclusion bias would severely affect the results of the trials, i.e., if patients likely to benefit from EVT had this treatment without being randomised. Another limitation in IMS III and Synthesis is that the detection of an occlusion of a major arterial trunk by CTA or MRA was not an inclusion criteria. In Synthesis, patients with very low NIHSS were included, but their evolution is most of the time favorable even without any treatment. Also no evaluation of the salvageable brain with perfusion CT or MR was made in IMS III and Synthesis and MR Rescue is inconclusive regarding the potential value of penumbra imaging.

IMS III, Synthesis, and MR RESCUE demonstrate that endovascular treatment is not appropriate for all patients with AIS. One very consistent and highly important finding from these trials is that endovascular treatment is as safe as IV rTPA, and there are no safety issues that should deter the evaluation of the thrombectomy approach in more refined trials. Future trials must focus on determining which treatments are the most efficacious and which patients will benefit from a particular treatment paradigm. A careful selection of patients will be necessary based on clinical status evaluated with NIHSS, initial extension of ischemic lesions evaluated with ASPECT score or other tools, arterial occlusion depicted by CTA or MRA or evaluation of the salvageable brain evaluated by methods that have still to be precisely evaluated. Patients with very low or very high NIHSS have to be excluded as well as patients without arterial occlusion detected with CTA or MRA. It would be probably more productive to design studies to evaluate a single endovascular approach rather than evaluating a wide spectrum of endovascular approaches in the same study. Also, comparison of the endovascular treatment alone to that of IV rTPA alone (as in Synthesis and MR RESCUE) demands a highly effective local organisation in order not to lose time before EVT can be initiated. The combined approach (EVT + IV rTPA) allows the physician to start treatment early and to synergise the efficacy of chemical and mechanical thrombolysis (this synergy has been suggested but has still to be demonstrated). Participation of both patients and physicians in RCTs is essential to provide rapid answers to this very important clinical problem.

Difficulty in the recruitment of patients was encountered in most RCTs dealing with endovascular treatment. This may in part explain the long time periods needed to complete them. Mechanical thrombectomy is not yet a validated treatment and by not including all eligible patients in an RCT physicians take the risk of skewing the results. Therefore, ongoing or future thrombectomy trials must address the requirements for centres enrolling patients. Selection of the participating centres in the future RCTs in terms of physician competency and organisation of the centres is certainly important to reduce the delay in the performance of EVT. It is also crucial that all patients meeting the inclusion criteria are included in the trial (consecutive enrolment). If a pre-selection is applied by the centre before randomisation, the risk is that certain patients eligible for IA treatment are not randomised (for “compassionate” reasons). This would create a serious inclusion bias and affect the results of the trial. As endovascular treatment has yet not proven its superiority to IV rTPA in a RCT, physicians cannot argue for treating patients outside of the trial.

 

Conflict of interest

LP consults for Codman, Covidien/EV3, Microvention, Penumbra and Sequent. MS consults for Rapid Medical, Neuravi, Covidien/ev3 and has a research agreement with Philips Healthcare. JG consults for Covidien/EV3. CC consults for Codman, Covidien/EV3, Microvention, Sequent and Stryker. PW has research activity funded from Acandis, Codman, Covidien/EV3 and Microvention; he consults for Microvention and has speaker bureau activities for Codman and Covidien/EV3. JF consults for Codman and Stryker and has speaker bureau activities for Covidien/EV3.

References

  1. Broderick JP, Palesch YY, Demchuk AM, et al.; Endovascular treatment after intravenous rTPA versus rTPA alone for stroke; N Engl J Med 2013; 368: 893-903.
  2. Ciccone A, Valvassori L, Nichelatti M, et al.; Endovascular treatment for acute ischemic stroke; N Engl J Med 2013; 368: 904-913. [PubMed] [Full Text Sources]
  3. Kidwell CS, Jahan R, Gornbein J, et al.; A trial of imaging selection and endovascular treatment for ischemic stroke; N Engl J Med 2013; 368: 914-923. [PubMed] [Full Text Sources]
  4. Von Kummer R, Gerber J. IMS III; Synthesis, and MR Rescue: no disaster, but down to earth; Clin Neuroradiol 2013; 23: 1-3.
  5. Meschia JF, Barrett KM, Brott TG; Reperfusion therapy for acute ischemic stroke: How should we react to the third Interventional Management of Stroke trial? Mayo Clin Proc 2013; 88: 653-657. [PubMed] [Full Text Sources]
  6. Pierot L, Gralla J, Cognard C, White P; Mechanical thrombectomy after IMS III, Synthesis, and MR Rescue; AJNR Am J Neuroradiol 2013; Jun 6 (Epud ahed of print).
  7. Pierot L, Söderman M, Bendszus M, White P, Muto M, Turjman F, Mangiafico S, Gralla J, Fiehler J, Szikora I, Cognard C; Statement of ESMINT and ESNR regarding recent trials evaluating the endovascular treatment at the acute stage of ischemic stroke; Neuroradiology. 2013; DOI 10.1007/s00234-013-1249-3 (in press).
  8. Fiehler J, Söderman M, Turjman F, et al.; Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR. Part I: Current situation and major research questions; Neuroradiology 2012;54:1293-301. [PubMed] [Full Text Sources]
  9. Fiehler J, Söderman M, Turjman F, et al.; Future trials of endovascular mechanical recanalisation therapy in acute ischemic stroke patients: a position paper endorsed by ESMINT and ESNR. Part II: Methodology of the future trials; Neuroradiology 2012;54:1293-301.
  10. Sutherland BA, Minnerup J, Balami JS, et al.; Neuroprotection for ischaemic stroke: translation from the bench to the bedside; Int J Stroke 2012 ; 7 : 407-418.
  11. Hacke W, Kaste M, Fieschi C, et al.; Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Stroke Study (ECASS); JAMA 1995; 274: 1017-1025. [PubMed] [Full Text Sources]
  12. Multicenter Acute Stroke Trial –Italy (MAST-I) Group; Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke; Lancet 1995; 346: 1509-1514. [PubMed]
  13. The National Institute of Neurological Disorders and Stroke rrTPA Stroke Study Group; Tissue plasminogen activator for acute ischemic stroke; N Engl J Med 1995; 333: 1581-1587.
  14. The Multicenter Acute Stroke Trial – Europ Study Group; Thrombolytic therapy with streptokinase in acute ischemic stroke; N Engl J Med 1996; 335: 145-150.
  15. Hacke W, Kaste M, Fieschi C, et al.; Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II); Lancet 1998; 352: 1245-1251. [PubMed] [Full Text Sources]
  16. Clark WM, Albers GW, Madden KP, et al.; The rtPA (Alteplase) 0- to 6-Hour Acute Stroke Trial, Part A (A0276g): Results of a double-blind, placebo-controlled, multicenter study; Stroke 2000; 31: 811-816.
  17. Clark WM, Wissman S, Albers GW, et al.; Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study – a randomized controlled trial; JAMA 1999; 282: 2019-2026. [PubMed] [Full Text Sources]
  18. Hacke W, Kaste M, Bluhmki E, et al.; Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke; N Engl J Med 2008; 359: 1317-1329. [PubMed] [Full Text Sources]
  19. Wahlgreen N, Ahmed N, Davalos A, et al.; Thrombolysis with alteplase 3-4.5 h after ischaemic stroke (SITS-ISTR) an observational study; Lancet 2008; 372: 1303-1309.
  20. Del Zoppo GJ, Higashida RT, Furlan AJ, et al.; PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke; Stroke 1998; 29: 4-11. [PubMed] [Full Text Sources]
  21. Furlan A, Higashida R, Wechsler L, et al.; Intraarterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial; JAMA 1999; 282: 2003-2011.
  22. The IMS study investigators; Combined Intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study; Stroke 2004; 35: 904-912.
  23. The IMS II trial investigators; The Interventional Management of Stroke (IMS) II trial; Stroke 2007; 38: 2127-2135.
  24. Ogawa A, Mori E, Minematsu K, et al.; Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke. The Middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan; Stroke 2007; 38: 2633-2639. [PubMed] [Full Text Sources]
  25. Smith WS, Sung G, Starkman S, et al.; Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial; Stroke 2005; 36: 1432-1438. [PubMed] [Full Text Sources]
  26. Smith WS, Sung G, Saver J, et al.; Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial; Stroke 2008; 39: 1205-1212. [PubMed] [Full Text Sources]
  27. Penumbra pivotal stroke trial investigators; The Penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease; Stroke 2009; 40: 2761-2768.
  28. Castano C, Dorado L, Guerrero C, et al.; Mechanical thrombectomy with the Solitaire AB device in large artery occlusions of the anterior circulation. A pilot study; Stroke 2010; 41: 1836-1840. [PubMed] [Full Text Sources]
  29. Costalat V, Machi P, Lobotesis K, et al.; Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the Solitaire device: a prospective 50-patient single–center study; Stroke 2011; 42: 1929-1935. [PubMed] [Full Text Sources]
  30. Soize S, Kadziolka K, Estrade L, et al.; Mechanical Thrombectomy in Acute Stroke: Prospective Pilot Trial of the Solitaire FR Device while Under Conscious Sedation; AJNR Am J Neuroradiol 2013; 34: 360-365. [PubMed] [Full Text Sources]
  31. Saver JL, Jahan R, Levy EI, at al.; Solitaire flow restoration device versus Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomized, parallel-group, non-inferiority trial; Lancet 2012; 380: 1241-1249.
  32. Nogueira RG, Lutsep HL, Gupta R, et al.; Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomized trial; Lancet 2012; 380: 1231-1240.