Treatment of Brain AVMs (TOBAS) Study
Treatment of Brain AVMs (TOBAS) Study
The objectives of this study and registry are to offer the best management possible for
 patients with brain arteriovenous malformations (AVMs) (ruptured or unruptured) in terms of
 long-term outcomes, despite the presence of uncertainty. Management may include
 interventional therapy (with endovascular procedures, neurosurgery, or radiotherapy, alone or
 in combination) or conservative management.

 The trial has been designed to test a) whether medical management or interventional therapy
 will reduce the risk of death or debilitating stroke (due to hemorrhage or infarction) by an
 absolute magnitude of about 15% (over 10 years) for unruptured AVMs (from 30% to 15%); and,
 b) to test if endovascular treatment can improve the safety and efficacy of surgery or
 radiation therapy by at least 10% (80% to 90%).

 As for the nested trial on the role of embolization in the treatment of Brain AVMs by other
 means: the pre-surgical or pre-radiosurgery embolization of cerebral AVMs can decrease the
 number of treatment failures from 20% to 10%. In addition,embolization of cerebral AVMs can
 be accomplished with an acceptable risk, defined as permanent disabling neurological
 complications of 8%.
Intracranial arteriovenous malformations (AVMs) are relatively uncommon but increasingly
 discovered lesions that can lead to significant neurological disability or death.1
 Population-based data suggest that the annual incidence of discovery of a symptomatic AVM is
 approximately 1.1 per 100 000 population.7. AVMs commonly present following an intracranial
 hemorrhage or seizure, although with contemporary brain imaging techniques, an increasing
 number of incidental lesions are found.2

 Intracranial AVMs are typically diagnosed before the age of 40 years old, with more than 50%
 of patients presenting following an intracranial hemorrhage, the most feared sequelae of
 harbouring an AVM.3 An AVM-related seizure is reported as the presenting feature in 20-25% of
 cases4, 5 and although these can sometimes be successfully managed with anti-epileptic
 agents, some AVMs lead to intractable seizures in spite of medication. Other presentations
 include headaches, focal neurological deficits, or pulsatile tinnitus.1

 The available natural history studies indicate an overall risk of initial hemorrhage of
 approximately 2% to 4% per year, although the long-term consequences in terms of the
 probability of death or long-term disability following intracranial hemorrhage remains
 unclear.6-8 Mortality from the first hemorrhage has been reported to occur between 10-30% of
 patients with a ruptured AVM, although some more recent data suggest that the mortality rate
 may be lower and only 10-20% of survivors have long-term disability.9-11 Hemorrhagic
 presentation is considered the most reliable risk factor for a repeat hemorrhage.6, 8
 Unfortunately, the natural history data available is not of sufficient quality (Level V) to
 support making management recommendations.

 Over the last decade, there have been substantial developments in the management of
 intracranial AVMs. There has been an evolution of microsurgical as well as endovascular and
 radiosurgical techniques to treat these lesions. As the management options have evolved,
 individual and combined modality treatment protocols have been developed in different
 institutions for the management of AVMs. Current interventional therapy for brain
 arteriovenous malformations (BAVMs) is varied and includes open neurosurgical resection,
 radiosurgery, and endovascular management, either alone or in combination. The choice of
 management is largely dependent on the decisions of the local physicians that make up the
 treatment team, and a recent survey has demonstrated substantial variability in
 decision-making for almost all AVMs.12

 Interventional therapies, when they are performed, are assumed to decrease the risk of
 initial or subsequent hemorrhage and therefore lead to better long-term outcomes, an
 assumption that has yet to be proven.

 Although the question of which AVM treatment modality is the most appropriate first choice
 (surgery, radiosurgery, or embolization) remains controversial, consensus can be reached in
 several circumstances. Surgical evacuation of a hematoma exerting significant mass effect is
 an uncontested appropriate management, although many patients with a hemorrhagic presentation
 do not necessarily meet this threshold for surgical indication. Almost all other management
 choices remain debatable.13, 14 A systematic review has proposed that approximately 7.1% of
 surgical candidates, 6.6% of endovascular candidates, and 5.1% of radiosurgical candidates
 were facing permanent neurological deficits after treatment.15 The epidemiological study of
 Davies et al, using the Nationwide Inpatient Sample (NIS) data base and surrogates such as
 location at discharge, showed worse outcomes for surgical and endovascular management of both
 ruptured and unruptured AVMs.16

 Current choices of interventional therapy for brain arteriovenous malformations are varied,
 with decisions made on a case-by-case basis, by the local clinical team. Often these
 decisions will change as the results of one particular attempted treatment modality become
 available. All interventional therapies are performed with the assumption that they will
 decrease the risk of initial or subsequent hemorrhage and lead to better long-term patient
 outcomes. Despite these laudable goals, there is no reliable evidence that interventional
 management of unruptured bAVMs is beneficial, and in patients judged to need interventional
 therapy, such as those patients presenting with ruptures, there is no randomized evidence
 that embolization is beneficial. Although no clinical trial data exist on the effect of
 interventional therapy even after AVM hemorrhage, the most contentious issue at present is
 whether interventional therapy should be considered for patients with incidentally discovered
 AVMs, whose lesions have not bled. In patients with unruptured AVMs, the best management
 strategy remains unknown, and interventions should be proposed only in the context of a
 randomized trial.

 The potential role of embolization: Although endovascular AVM embolization can occasionally
 eradicate lesions without surgery or radiation therapy in selected cases, and although
 embolization may potentially improve the safety and efficacy of surgical or radiosurgical
 treatments in some other cases, it remains a contentious issue whether it is worth accepting
 the additional risks of endovascular treatment for a greater overall benefit for patients
 with brain AVMs that are treatable by surgery or radiation therapy. Some series have reported
 satisfactory results.20 It is possible that the overall morbidity and mortality of the
 combined interventional management strategy is increased when embolization is added to a
 surgical or radiosurgical procedure.17 Therefore, pre-surgical or pre-radiosurgical
 embolization can be offered, but only as a randomized allocation between embolization and no
 embolization, within the context of a trial.

 Primary objective: In the spirit of care trials, the primary objective of the trial and
 accompanying registry is to offer the best management possible for patients with brain AVMs
 (ruptured or unruptured) in terms of long-term outcomes, despite the presence of uncertainty.
 Management may include interventional therapy (neurosurgery, or radiosurgery, alone or in
 combination, with or without endovascular procedures, alone or combined) or conservative
 management. An expert multidisciplinary study group will review patients on an individual
 basis to determine eligibility for the trial or registry parts of the study. The trial has
 been designed to test whether conservative management or interventional therapy will reduce
 the risk of disabling stroke or death.

 Secondary objectives: To determine if interventional management is effective in the
 prevention of neurological events during 10 years. To determine the morbidity and mortality
 related to therapy. To follow-up and record the neurological events and the neurological
 status of all patients with brain AVMs recruited and managed in our institutions, regardless
 of management strategy chosen.

 Hypotheses

 A) Randomized comparison of interventional treatment and conservative management:

 Primary hypothesis: Treatment of cerebral AVMs can decrease the number of disabling
 neurological events caused by the presence of the AVM (excluding peri-operative
 complications) from 30 to 15% within 10 years. (n = 266 minima) Secondary hypothesis:
 Treatment of cerebral AVMs can be accomplished with an acceptable up-front risk, defined as
 the occurrence of a permanent disabling neurological complication in less than 15% of
 patients)

 B) Nested trial on the Role of embolization in the treatment of Brain AVMs by other means
 Primary hypothesis: Pre-surgical or pre-radiosurgery embolization of cerebral AVMs can
 decrease the number of treatment failures (failure to achieve angiographic cure) from 20% to
 10% (n= 440).

 Secondary hypothesis: Embolization of cerebral AVMs can be accomplished with an acceptable
 risk, defined as permanent disabling neurological complications of 8% (3.4 to 12.6%, 95%
 C.I.).

 The study design is a prospective, multi-center, randomized, controlled trial and registry.
 Treatment assignment will not be masked; Interim study results will be kept confidential. The
 primary outcome is the composite event of death from any cause or disabling stroke
 (hemorrhage or infarction revealed by imaging and resulting in mRS >2). Functional outcome
 status will be measured by the Rankin Scale, a widely used outcome measure for stroke. The
 secondary measures of outcome include adverse events, ruptures, and angiographic occlusion of
 the lesion.
Inclusion Criteria:

 -  Any patient with a brain AVM

 Exclusion Criteria:

 -  Hemorrhagic presentation with mass effect requiring surgical management. In these
 cases, if a residual AVM is found after the initial surgery, the patient could then be
 a candidate for TOBAS.