Treatment of Brain AVMs (TOBAS) Study

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.