There are several factors that distinguish patients with BAO from those with middle cerebral artery (MCA) occlusion that may warrant a different treatment approach:
Severity of deficit: previous studies have suggested a greater benefit of IA therapy in patients with a severe deficit.
High poor outcome rate: because of a higher poor outcome rate, patients with BAO have more to gain.
Collateral flow: the basilar artery not only receives collateral flow through cortical cerebellar branches, comparable to the cortical hemispheric branches of the MCA, but also by retrograde filling by the anterior circulation through the posterior communicating arteries as part of the circle of Willis. IVT may be more effective in the presence of good collateral flow, by attacking the thrombus from both sides.
Time window for treatment: the BASICS registry data suggest the presence of a longer time window from symptom onset to time of treatment. The PROACT studies used a limit of time from symptom onset to time of treatment of 6 h [4, 17]. The IMS III study used a 5-h time window from symptom onset to initiation of IAT . The BASICS trial uses a 6-h time window from estimated time of BAO to initiation of IA treatment. The BASICS registry used the estimated time of symptom onset consistent with the clinical diagnosis of BAO to treatment rather than the more commonly used time of onset of any symptoms to treatment. Previous studies have shown that BAO is preceded by prodromal symptoms in >60% of patients [19, 20]. Most of these patients would be excluded from a potential trial using the time of onset of first symptom <4.5 h to treatment as an inclusion criterion. We believe that the results from the BASICS registry support the use of the estimated time of BAO rather than using the time of onset of any symptom to treatment as an inclusion criterion for the BASICS trial.
IVT versus IVT/IAT comparison: IV thrombolysis is the current standard of care in patients presenting with acute ischaemic stroke with a proven safety and efficacy and therefore should be regarded as the current ‘Gold Standard’ with which potential new treatment strategies should be compared.
The use of an IVT only arm in a trial of patients with acute symptomatic BAO is supported by the results of the BASICS registry in which no significant difference was found between IVT or IAT treated patients with a severe deficit .
The performance of a trial comparing IVT alone vs. IAT alone in patients with BAO does not seem feasible nor ethical. Referral of a patient to an intervention centre for randomisation between IVT vs. IAT alone would mean delaying the initiation of a treatment which is of proven benefit - whereas there is convincing evidence for the principle of ‘time is brain’, also in patients with BAO [21, 22]. The number of patients with BAO presenting directly to an intervention centre will be too limited. Patients with BAO only represent an approximate 5% of all IVT eligible patients, and only 40% of patients in the BASICS registry where admitted directly (without referral) to an intervention centre.
In order to include a sufficient number of patients the BASICS trial will therefore mainly depend on the inclusion of patients referred from non-intervention community hospitals. The non-intervention hospitals are encouraged to start IVT without delay before sending the patient with the clinical diagnosis of BAO to the intervention centre.
A combined IV and IA approach to acute ischaemic stroke therapy was designed to offer rapid initiation of IV rt-PA, followed by additional titrated local IA therapy, to patients with moderate-to-severe strokes (NIHSS ≥10). The goal was to achieve higher rates of early, successful reperfusion in a widely accessible manner. This approach has been tested in clinical trials of >200 patients, starting with the Emergency Management of Stroke (EMS) pilot trial from 1995 to 1996, followed by the Interventional Management of Stroke (IMS) I trial in 2001, the IMS II trial from 2003 to 2006, and several additional cohorts [23–25]. The data from EMS and IMS show that the combined approach to recanalisation may be more effective than standard IV rt-PA alone for moderate-to-severe (NIHSS ≥10) strokes, while maintaining a similar safety profile. The recently published IMS III trial data did not show a significant difference in outcome comparing IV rt-PA with IV rt-PA followed by IAT in patients with a NIHSS of 8 or greater treated within 3 h . Few patients with BAO were included, about 2% in both treatment arms. Furthermore, few patients had radiologic confirmation of occlusion and most patients in the IA arm were treated with IA thrombolysis or first generation thrombectomy devices, much less effective than the currently used stentretrievers [27, 28].
The 4.5-h time window is based on the results of the ECASS III study . A time window of 0–4.5 h from symptom onset to treatment in patients with acute ischaemic stroke is widely accepted. The BASICS registry results show the safety of using a 0 to 4.5-h time window from estimated time of occlusion to treatment in patients with acute BAO .
IVT + IAT arm
Based on the results of the PROACT studies the 6-h time window for IA thrombolysis in patients with MCA occlusion is widely accepted [4, 17].
A case series of 69 patients treated with IA thrombolysis (urokinase, reteplase or alteplase) following full dose IVT showed the safety of full dose IVT followed by IA thrombolysis. Symptomatic haemorrhage occurred in four out of 69 (5.8%) patients .
The MERCI studies suggested safety of mechanical thrombectomy up to 8 h from symptom onset . The BASICS study shows that a time window of 0 to 6 h from estimated time of occlusion to IA treatment is safe in patients with a severe deficit while little can be gained in both IVT and IAT treated patients beyond the 6-h time window .
The main theoretical advantage of an IA approach is the variety of treatment options, which can be tailored to the individual patient. Because of the variety in approved IA treatment options and the limited number of patients, the experience with specific devices or thrombolytics varies considerably among stroke centres both within and between countries. Limiting the use of treatment options would exclude centres from participation because of lack of experience with the selected device or thrombolytic despite ample experience in the use of alternative devices or thrombolytics. New devices or thrombolytics that become available during the study may be used in the IAT arm depending on national and local approval and experience. Prior approval by the steering committee needs to be obtained.
The Steering Committee carries the ultimate responsibility for the trial. Specific tasks of the steering Committee are: (1) approval of the study protocol; (2) approval of amendments to the study protocol; (3) deciding whether or not to continue the trial based on the recommendation of the DMSB; (4) reviewing protocols for satellite studies; and (5) approval of reports and publication of the trial.
As of 18-10-2012, members of the Steering Committee are (in alphabetical order):
A. Algra*, clinical epidemiologist, University Medical Center Utrecht, Utrecht, the Netherlands;- H.J. Audebert*, neurologist, Charité Berlin, Berlin, Germany; E. Berge, neurologist, Oslo University Hospital Ullevål, Oslo, Norway; A. Ciccone, neurologist, Carlo Poma Hospital, Mantua, Italy; L.J. Kappelle*, neurologist, University Medical Center Utrecht, Utrecht, the Netherlands; M. Mazighi, interventional neurologist, Bichat University Hospital, Paris, France; P. Michel*, neurologist, University Medical Centre Vaudois, Lausanne, Switzerland; K.W. Muir, neurologist, University Medical Centre Glasgow, Glasgow, United Kingdom; V. Obach, neurologist, Clinic Hospital Barcelona, Barcelona, Spain; V. Puetz, neurologist, Dresden Stroke Centre, Dresden, Germany; W.J. Schonewille*, neurologist, St. Antonius Hospital, Nieuwegein, the Netherlands, principal investigator; J.A. Vos*, interventional radiologist, St. Antonius Hospital, Nieuwegein, the Netherlands, co-principal investigator; C.A.C. Wijman†, neurologist, Stanford University Medical Centre, Palo Alto, CA, USA; A. Zini, neurologist, St. Agostino-Estense Hospital, Modena, Italy.
* Also member of the Executive Committee
As of 18 October 2012, members of the Executive Committee, who are responsible for the trial on a day-to-day basis, are all members of the Steering Committee indicated with an * and E.J.R.J. van der Hoeven, radiology resident, St. Antonius Hospital, Nieuwegein, the Netherlands, coordinating investigator.
Trial Coordination Centre
The Trial Coordination Centre is located at the Neurology department in the St. Antonius Hospital Nieuwegein in the Netherlands.
Data Safety and Monitoring Board
An independent Data Safety and Monitoring Board, consisting of clinicians familiar with the treatment of stroke, a biostatistician and a neuro-interventionalist, has been established to monitor the progress of the trial. Details on the advice(s) of the DSMB will be notified to the Steering Committee and the METC that approved the protocol. With this notification a statement will be included indicating whether the advice will be followed.
As of 15 April 2011, members of the Data Safety and Monitoring Board, are (in alphabetical order): K.T. Hoffmann, interventional radiologist, University of Leipzig, Leipzig, Germany; P. Lyden, neurologist, Cedars-Sinai MC, Los Angeles, CA, USA (Chair); R. Raman, Biostatistician, University California, San Diego, CA, USA; D. Toni, neurologist, University ‘La Sapienza’, Rome, Italy.
The trial started in October 2011 in the coordinating centre, the St Antonius Hospital Nieuwegein with the inclusion of the first patient. Eleven other centres in the Netherlands, Switzerland, Czech Republic and Italy have joined since then. As of July 2013 21 patients have been randomised. In Germany, France and Spain the protocol is awaiting national ethical approval. Several other Dutch, German, French, Czech, Swiss, Italian, Spanish and Norwegian centres have indicated that they are interested in participating (http://www.basicstrial.com).