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.