Thrombolysis Or Anticoagulation for Cerebral venous Thrombosis

Cerebral venous thrombosis (CVT) is a distinct subtype of stroke that mainly
affects young and middle aged patients. While it is a relatively rare disease
with an overall adult incidence of approximately 5 cases per million, it does
account for 5% of all strokes in adults younger than 45. The most important
complications of CVT are venous infarcts (50% of patients) and seizures (40%).
Despite heparin treatment, which is now generally accepted as first-line
treatment for CVT, 22% of patients remain handicapped or die. Large prospective
cohort studies have resulted in the identification of a number of risk factors
that predict a high probability of poor outcome. In approximately 30% of all
CVT patients one or more of these risk factors is present and 40% of these
patients remain handicapped or die. More aggressive treatment strategies, such
as endovascular thrombolysis, might be warranted in this subset of patients.
Endovascular thrombolysis aims to dissolve the existing thrombus by application
of a thrombolytic substance within the occluded sinuses, which may result in a
more rapid venous recanalization. Published experience with endovascular
thrombolysis for treatment of CVT is promising, but is only based on case
reports and small case series. Most experts therefore believe that a randomized
clinical trial is urgently needed.

The objective of this study is to determine the clinical efficacy of
endovascular thrombolytic treatment (ET) as compared to standard treatment (any
therapeutic heparin regimen) in patients with proven cerebral venous sinus
thrombosis and a high chance of poor outcome.

The study will be an international, multicenter prospective, randomized,
open-label, blinded endpoint (PROBE) trial. A blinded, placebo controlled trial
is unethical due to the invasive nature of an endovascular procedure. To
minimize the risk of bias associated with an open-label study, the primary and
secondary endpoints will be assessed by a trained nurse or neurologist who is
blinded to the treatment allocation. The PROBE design has the additional
advantage that the effect of treatment will be tested as it will be provided in
clinical practice.

Eligible patients who give their informed consent are randomized (1:1 ) to
receive either
- Investigational treatment: endovascular thrombolytic treatment
- Standard care: (continuation of) any therapeutic heparin regimen.

Investigational treatment: Thrombolytic procedure
Various methods for endovascular thrombolysis for CVT exits. The TOACT trial
does not prescribe an explicit protocol for ET that must be used. The exact
thrombolytic procedure is a decision of the local investigators, and should
comply with local procedures and experience. The minimum requirement is that a
catheter is introduced into one or more thrombosed sinuses under angiographic
control. The interventionalist may use either alteplase or urokinase as a
thrombolytic drug. The combined use of rt-PA and urokinase in a single patient
is not allowed. The thrombolytic drug must be infused directly into the
thrombosed sinus. The use of bolus infusions, as well as the duration and
dosage of the thrombolytic treatment is the decision of the local investigators
and may vary according to the degree of recanalization achieved. Continuous
local infusion in the cerebral sinus by leaving a catheter in situ is allowed
and at the discretion of the interventionalist, as is the use of standard
endovascular mechanical methods of clot disruption and removal. Anticoagulation
during thrombolytic procedure with heparin (LMWH or unfractionated heparin) is
preferable, but not mandatory, and is up to the local investigator. All local
investigators should submit a local thrombolysis protocol from their own
department for central review and approval before they can join the study. The
interventionalist performing the procedure must be experienced in
neuro-endovascular techniques. In addition, experience with either ET for CVT
or ischemic stroke is required.

Standard care: Heparin
The patients randomized to standard care will receive (or continue) either
intravenous adjusted dose unfractionated heparin (aPTT value kept within 1.5 to
2.5 times the normal value), or any type of body-weight adjusted low molecular
weight heparin in therapeutic dose, according to local custom and international
guidelines. All investigators must submit a local heparinisation protocol for
central approval before they can join the study.

Based on published results regarding the use of endovascular thrombolysis in
CVT patients, there are some indications that this therapy is beneficial for
the treatment of CVT. Patients included in the trial have a 50% of receiving
endovascular thrombolysis. These patients therefore may directly benefit from
the study. The potential complications that may occur during endovascular
thrombolysis are the most important risk of the study. These potential
complications are described in paragraph E9.

After discharge, patients will be examined at the outpatient clinical twice,
once after 6 months and once after 12 months. During these follow-up moments
patients will be interviewed and will receive a standard physical examination.

Before the 6 month follow-up visit, all patients will undergo cerebral imaging
one time to determine recanalization rate. MRI will used for this purpose, but
if MRI is unavailable, or not possible, CT-scanning with venography will be
used.