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Commentary
Too much guidance
  1. David Fiorella1,
  2. J Mocco2,
  3. Adam S Arthur3,
  4. Sean Lavine4,
  5. Felipe C Albuquerque5,
  6. Don Frei6,
  7. Raymond D Turner7,
  8. Aquilla Turk8,
  9. Adnan H Siddiqui9,
  10. William J Mack10,
  11. Andrei Alexandrov11,
  12. Joshua A Hirsch12,
  13. Robert W Tarr13
  1. 1Department of Neurosurgery, State University of New York at Stony Brook, Stony Brook, New York, USA
  2. 2Mt Sinai Hospital, NYC, New York, USA
  3. 3University of Tennessee, Semmes-Murphey Neurologic and Spine Clinic, Memphis, Tennessee, USA
  4. 4New York-Presbyterian Hospital, New York, USA
  5. 5Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona, USA
  6. 6Department of Interventional Neuroradiology, Radiology Imaging Associates, Englewood, Colorado, USA
  7. 7Department of Neurosciences, Medical University of South Carolina, Mount Pleasant, South Carolina, USA
  8. 8Medical University of South Carolina, Charleston, South Carolina, USA
  9. 9Departments of Neurosurgery and Radiology and Toshiba Stroke Research Center, University at Buffalo, State University of New York, Buffalo, New York, USA
  10. 10Department of Neurosurgery, University of Southern California, Los Angeles, California, USA
  11. 11Department of Neurology, University of Tennessee, Memphis, Tennessee, USA
  12. 12NeuroEndovascular Program, Massachusetts General Hospital, Boston, Massachusetts, USA
  13. 13Department of Radiology, University Hospitals Case Medical Center, Ohio, Ohio, USA
  1. Correspondence to Dr David Fiorella, Department of Neurosurgery, State University of New York at Stony Brook, Stony Brook, NY 11794-8122, USA; David.Fiorella{at}sbumed.org

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The unambiguous benefit of thrombectomy in patients with emergent large vessel occlusion (ELVO) has now been demonstrated in five multicenter, prospective, randomized controlled trials.1–5 These trials ended just months after three randomized controlled trials had shown no benefit for thrombectomy.6–8

The positive trials differ from the negative trials in three important ways. First, modern thrombectomy devices (primarily stent retrievers) were used in each of the positive trials. Patients in the negative trials were primarily treated with intra-arterial thrombolytic infusions and the MERCI device, which have been shown to be much less effective in achieving an effective revascularization. Second, the positive trials mandated vascular imaging to confirm large vessel occlusion before enrollment. Confirmation of large vessel occlusion was a requirement for only the smallest of the earlier negative trials. A subsequent subgroup analysis of the largest trial indicated that for those patients with confirmation of large vessel occlusion there appeared to be a benefit for thrombectomy. Third, with experience derived from prior studies, the exclusion of patients with large areas of completed infarct and little likelihood of improving after endovascular therapy was recognized to be of critical importance. In three of the five positive trials, advanced imaging applications were incorporated into the screening process to help investigators exclude patients with large areas of completed infarction, and the others used either a ‘grey principle’ or the ASPECTS score to allow proceduralists to screen patients before enrollment. There were other differences in the design of the positive trials, but these three major differences, largely consistent across trials, accounted for their overwhelming and uniform positivity.

These data have resulted in an immediate and dramatic shift in evidence-based stroke care. The rapidity with which this change has occurred underscores the astounding rate at which neuroendovascular therapies have developed and, for the foreseeable future, will continue to evolve.

The American Heart Association (AHA) guidelines for stroke treatment were recently modified to reflect the data from these new trials.9 These guidelines recommend thrombectomy for patients with ELVO within 6 h, but also specify that thrombectomy should be performed with a ‘stent retriever device’. The inclusion of such a device-specific recommendation is somewhat unusual, unnecessarily restrictive, and short-sighted.

Neuroendovascular therapies continue to evolve rapidly. Devices have become lower profile, easier to deliver, easier to use, and more effective. Just as with the evolution from MERCI to stent retrievers, sometimes the mechanism and structure of the new devices bear little resemblance to their predecessors and involve new techniques. Aspiration thrombectomy, using the ADAPT technique, has joined stent retrieval as a front-line approach to interventional stroke therapy in many high volume centers around the world.10 ,11 Additional iterative and innovative advances in thrombectomy will surely follow. Thus, while these new data clearly show, for the first time, that efficient thrombectomy is beneficial in ELVO, they do not indicate that this end can be achieved only with a single tool or technical approach.

It is not practical to insist that all iterations of new devices and techniques be validated in prospective, randomized controlled trials versus stent retrievers. In the recent past, the MERCI thrombectomy device and medical management both provided a relatively low bar for comparison. The high efficacy of stent retrievers (the active control) in achieving revascularization makes future comparative trials prohibitive, even were they to use a non-inferiority design. Mandating such a level of evidence in our relatively small field would dramatically increase both the cost and time required for bringing new thrombectomy devices to market and these barriers would hamper improvements in clinical outcomes.

The Food and Drug Administration (FDA) faces the challenging task of ensuring that robust regulatory processes are in place, without obstructing the rapid delivery of safer and more effective tools. There will be challenges ahead in determining appropriate mechanisms for approval and postmarket surveillance for new stroke devices.

It is unrealistic to imagine that the guidelines for stroke therapy will be continually rewritten to certify each new iteration of effective thrombectomy technology or technique approved by the FDA. Indeed, this approach is in sharp distinction to prior AHA guidelines. The AHA guidelines for intervention in acute ST segment elevation myocardial infarction do not delineate a specific tool for endovascular revascularization, but merely outline those situations in which percutaneous coronary intervention is indicated and those in which coronary artery bypass graft surgery is the preferred method.12 ,13 We believe a similar approach is appropriate for ELVO and it should emphasize rapid identification of patients with ELVO at any level facility accepting stroke victims, time-to-comprehensive stroke center notification, development of regional systems of care and shorter transfer times, time-to-puncture, and time-to-reperfusion as opposed to specific devices and overall time window eligibility constraints.

Provided that operators are achieving revascularization results comparable to, or better than, those reported for stent retrievers there is no reason to limit practice with newer and potentially better thrombectomy device technologies or approaches. Although there is almost no risk of any experienced operator reverting to an obsolete technology such as MERCI, it is of no harm to specify within the guidelines that the MERCI device should not be used for thrombectomy. On the contrary, by issuing guidelines that specify that stent retrievers should be used preferentially, we are placing those treating ELVO at unnecessary and unreasonable medicolegal risk should they choose to employ a new or alternative (FDA cleared) device/technique.

Moreover, while expeditious to refer to the modern, positive thrombectomy trials as the ‘stent retriever trials’, this approach is not evidence-based. Such an approach ignores the other important differences between the new group of trials and their predecessors. We must acknowledge that the two largest of the positive thrombectomy trials were device/technique neutral (ESCAPE, MR CLEAN). In the more recent trials, stent retrievers were sometimes used in combination with distal access catheters with an aspiration thrombectomy technique (‘Solumbra’). Moreover, THERAPY, a study which was terminated early owing to loss of equipoise with respect to the randomization of patients with ELVO versus medical therapy, showed that aspiration thrombectomy yielded technical and clinical results which were comparable to those achieved with stent retrievers.14

For these reasons, we recommend guidelines that do not mandate a specific device or technical approach, but rather allow the operator to perform thrombectomy in the safest and most efficacious manner for a given patient.

Patients with ELVO are a heterogeneous group united by their desperate need for rapid and effective revascularization.15 We must ensure that we maintain an environment that will allow us to continually optimize our interventions in these patients. There is still a long way to go….

References

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Footnotes

  • Correction notice This article has been corrected since it published Online First. The competing interest statement has been amended and the author Sean Lavine's name corrected.

  • Competing interests JM: consultant – Lazurus Effect, Reverse, Pulsar, Edge Therapeutics, Medina; investor – Blockade Medical, Medina, Lazurus Effect. ASA: research support – Sequent and Siemens; consultant – Microvention, Johnson and Johnson, Medtronic, Penumbra, Silk Road, Stryker, Sequent; stock – Lazarus Effect and Valor. DF: consultant – Medtronic/Covidien, Stryker, Penumbra, Codman, Siemens. RDT: consultant – Penumbra, Covidien/Medtronic, Codman, Blockade, Pulsar vascular, Microvention. AT: consultant and research grant – Stryker, Penumbra, Microvention; research grant – Medtronic; consultant and shareholder – Medina Medical, Lazarus Effect, Pulsar Vascular. AHS: consultant – Codman & Shurtleff Inc, Covidien Vascular Therapies, GuidePoint Global Consulting, Penumbra, Stryker, Pulsar Vascular, Microvention, Lazarus Effect, Blockade Medical, Reverse Medical, WL Gore & Associates, Medina Medical, Cervetech Inc, Neuroavi, Perflow Medical, Silkroad Medical, TRES Medical, Syntervention; research grants – The National Institutes of Health; financial interests – Hotspur, Intratech Medical, StimSox, Valor Medical, Blockade Medical, Lazarus Effect, Pulsar Vascular, Medina Medical Inc; national steering committees – Penumbra, 3D Separator Trial, Covidien, SWIFT PRIME Trial, LARGE Trial, POSITIVE Trial, Codman, BRAVO Trial, Neuroavi, ARISE II Trial; advisory board – Codman & Shurtleff, Covidien Neurovascular, Inter-societal Accreditation Commission. WJM: consultant – Medtronic (DSMB), Penumbra (DSMB), Lazarus Effect. AA: speaker bureau – Genentech. JAH: consultant – medtronic; shareholder – Intratech.

  • Provenance and peer review Commissioned; internally peer reviewed.

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