An overestimated study,
crippled by recruitment failure
and misleading conclusions

Bernhard H.J. Juurlink,1
Pietro M. Bavera,2 Salvatore Sclafani,3
Ivo Petrov,4 Donald B. Reid5

A recent study, published in JAMA
Neurology, examining whether using percutaneous
transluminal angioplasty (PTA) to
correct chronic cerebrospinal venous insufficiency
(CCSVI) in multiple sclerosis
(MS) patients concluded: Venous PTA has
proven to be a safe but largely ineffective
technique; the treatment cannot be recommended
in patients with MS. 1 This is rather
a bold statement for a study that was grossly
underpowered. Not surprisingly, given the
history of reaction to the idea that impairment
of venous return might influence the
progression of MS, the publication of this
study was followed by several editorials
that bemoaned the power of social media to
influence research on and treatment of disease.
2,3
The Brave Dreams clinical trial was a
multi-centre, randomized, sham-controlled
evaluation of the efficacy and safety of
venous PTA of extra-cranial and extra-vertebral
veins that contributed to CCSVI in
patients with MS.1 Involved were six centres
accredited by the Italian National
Health Service. Only physicians trained and
accredited in functional outcomes, operation
of Echo Colour Doppler (ECD) and
catheter venography with and without PTA
participated. Patients in the trial were
between 18 and 65 years old who had a
diagnosis of remitting relapsing (RR) or
secondary progressive (SP) MS with
Extended Disability Status Scale (EDSS)
score between 2 and 5.5, disease duration of 15 years or less, a stable neurology condition
for at least 30 days, CCSVI as determined
by ECD, not having received MSspecific
treatment for at least six months, no
prior PTA nor having a history on being on
certain medications such as fingolimod.
The primary outcomes measured at 12
months were a functional composite score
and MRI-detectable lesions. A new functional
composite score was developed based
upon commonly-experienced functional
impairments such as walking control, balance,
manual dexterity, post-void residual
urine volume, visual acuity, etc. Patients
were evaluated and placed into improved,
stable, worsened or mixed categories. MRI
analysis grouped patients into categories
having new and/or enlarged lesions compared
to baseline and those free of lesions.
Secondary outcomes included annualized
relapse rates, changes in EDSS score and
proportion of patients with restored venous
flow.A power analysis was performed that
determined that to detect 2.1 fewer lesions
in RR MS patients at 90% power (an a of
0.05) would require the enrollment of 423
patients and at an 80% power would require
enrollment of 300 patients. For SP MS
patients a 90% power would require recruiting
222 patients. How many patients were
actually enrolled in the clinical trial? Only
115 RR MS patients enrolled in the study, of
whom 112 completed the study while only
15 SP MS patients were enrolled. Herein
lies the major problem of the study: gross
underpowerment. This incomplete study
should not have been published, rather additional
centres should have been established
to ensure adequate patient enrolment.
What the study found was that there
were essentially no differences in functional
composite score between the PTA and Sham
groups of RR MS. However, 73% of the
PTA group had no new gadolinium-enhancing
lesions compared to 49% in the Sham
group (P=0.08). For secondary endpoints
the study showed that 23% of PTA had at
least one relapse (annualized rate of 0.32)
compared to 31% (annualized rate of 0.39)
of the Sham group but this was not a significant
difference.
With SP MS there were no differences
in composite functional score between the
two groups; however, 100% of the PTA
group (n=10) developed no new lesions as
opposed to 40% in the Sham group (n=5).
In summary, there was a trend for fewer
new lesions in both the RR and SP MS
groups if they had PTA and fewer relapses
in the PTA group of RR MS patients.
However, there were no differences noted
between the two groups for composite functional
and EDSS scores. About 41% of the RR improved compared to 49% of the
Sham while 12% of the RR and 19% of the
Sham worsened with the remaining patients
showing a mixed outcome. Curiously,
median EDSS scores decreased from a
median score of 2.5 to 2.0 in both the PTA
and Sham-treated groups.
What would the results have been if the
study was properly powered? We point out
that in a large study where 366 MS patients
who had PTA to correct for CCSVI were
followed up for 4 years, PTA resulted in significant
clinical improvement, especially in
the RR MS patient group.4,5 The patients
were divided into RR (264), Primary
Progressive (PP) and SP groups. All
patients underwent a Duplex exam and
filled out a Questionnaire that addressed the
following symptoms: diplopia, fatigue,
headache, upper limb numbness/mobility,
lower limb numbness/mobility, altered thermic
sensibility, bladder control, balance
coordination, quality of sleep, vertigo, mind
concentration and working activity. Patients
with CCSVI then underwent PTA and were
followed up for 4 years. It is important to
note that the researcher carrying out the
Duplex exams and analyzing the
Questionnaire data was completely independent
of the vascular surgeons carrying
out the PTA. This large study demonstrated
that in RR MS patients that venous blood
flow improvements were long-lasting when
the abnormalities were not so severe.
Further, improved venous outflow was associated with long-lasting improvements
in clinical symptoms with improvements in:
more than 90% with diplopia, fatigue,
headache, quality of sleep, vertigo and ability
to mentally concentrate; more than 80%
in balance control and upper and lower limb
functions; and more than 65% in bladder
control and thermic sensibility. In contrast,
although SP and PP MS patients showed
some initial clinical improvements following
angioplasty, these disappeared within 2-
12 weeks.
A problem with the Brave Dreams
study is that only about half of the patients
had improved venous blood flow following
PTA. Clearly, the reasons underlying this
surprising failure to improve blood flow in
almost 50% of the patients treated for
CCSVI must be investigated. The authors
are encouraged to publish a review of the
technical methodology and outcomes of
their study so that the techniques can be
analyzed and enhancement in technique be
considered. It is equally important to delineate
which subset of MS patients respond to
PTA. We point out that carotid endarterectomy,
which now is a well-accepted common
stroke prevention technique in a subset of
patients, was questioned as recently as
1984.6 The challenge in determining efficacy
of endarterectomy was to define which
subset of patients benefited from the
surgery. This has now been clarified.7 Those
who have performed angioplasty to correct
for CCSVI in MS patients have noted that
only a subset of patients benefits from treatment.
More research is needed to identify
the subset of MS patients with CCSVI that
can benefit from the treatment.
What also struck us was the lack of
composite functional endpoint analysis of
the subset of PTA-treated patients (54%)
where blood flow improved compared to
the patients where blood flow was not
improved? After all, one of the objectives of
PTA in treating CCSVI is improvement of
venous outflow and cerebrospinal fluid
drainage to ultimately enhance cerebrospinal
perfusion. And, as noted above, in
the Bavera follow-up study clinical
improvements were noted only if there were
improvements in venous outflow following
PTA.4,5 Further, why was no attention paid
to the fact that 38% of the sham-treated
group had improved blood flow, after all
improved blood flow regardless of treatment
is desired to improve symptoms of
MS. Improved blood flow following shamtreatment
is, at first glance, surprising; perhaps
valvular and other endoluminal alterations
resulting from catheterization itself
may improve flow. Moreover, there is some
evidence suggesting that PTA may improve
autonomic function which may itself improve blood flow.8,9 If this be the case
then it becomes important to know whether
improved venous blood flow, regardless of
treatment, improves outcomes. This was not
addressed in the paper.
The possibility of technical deficiencies
must be considered as a contributor to the
poor rate of flow restoration in the Brave
Dreams study. Reporting clinical outcomes
of a new operative procedure without also
reporting the technical parameters of the
procedure as was recommended by the
International Society for Neurovascular
Disease (ISNVD) and by the Society of
Interventional Radiology prevents real critique
of the procedure.10,11 Many aspects of
this therapy are dependent on the diagnostic
findings, such as use of intravascular ultrasound,
degree of stenosis, number of extrinsic
compressions, incidence of webs, divisum,
septum duplication and webs, transit
time, stagnation, reflux, and as well upon
technique, such as balloon size versus vessel
size, end point of angioplasty, pressure
of angioplasty, number of inflations, duration
of inflation, residual stenosis, incidence
of dissection. Without this information, proceduralists
cannot assess the validity of the
results, or learn why almost half of the
patients failed to have improved flow after
angioplasty, nor can they develop improvement
in techniques.
One firm conclusion from this randomized,
blinded study is that PTA to correct for
CCSVI is safe.1 This is not a new finding
since the safety of PTA to correct for
CCSVI had been described previously.12We
also note that if one combines the
Remitting-Relapsing and the Secondary
Progressive MS patients in the PTA (n=73
and n=10, respectively) and Sham (n=37
and n=5, respectively) and examines for
absence of new lesion formation, we find
that 56/83 PTA patients and 21/42 Sham
patients had no new lesions. A Chi Squared
analysis shows that the probability of the
PTA treatment having no effect is 0.058. As
noted this Brave Dreams study was greatly
underpowered and this statistical analysis
suggests that on this basis alone further
studies are well-warranted and we urge the
investigators to continue to enrol patients
into their clinical trial and to, especially, dig
deeper into the data. There is an abundance
of evidence that co-morbidities have an
effect on progression to disability in MS13
and it is, therefore, not unreasonable to
hypothesize that problems in venous outflow
from the CNS would affect progression
to disability.

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