ICSS
International Carotid Stenting
Study
Protocol
Version 3.15
Contents
International
Carotid Stenting Study Protocol
Participating
centre requirements
Investigations
before randomisation
Sample
size calculations and recruitment
Principal
research questions to be addressed
Effect
of changes in technology during the course of the study
Health
service research issues
External
Adjudicators for Outcome Events
Trial
Data Monitoring Committee
Collaboration
between ICSS, SPACE and EVA-3S
Address
and contact numbers for further enquiries
Background:
Clinical trials have shown that carotid surgery prevents stroke but also has
significant morbidity. Stenting has become an established alternative treatment
for coronary and peripheral vascular disease and has the advantage of avoiding
general anaesthesia and neck incision. In July 1997, randomisation was completed in the Carotid and Vertebral
Artery Transluminal Angioplasty Study (CAVATAS). The results did not show a
difference in the major risks or benefits of carotid angioplasty and surgery,
but the trial did show that both methods still carry a significant risk of
causing a stroke. Techniques of carotid angioplasty have improved and stenting
is increasingly used. The International Carotid Stenting Study (ICSS or CAVATAS
2) is a follow-on study to CAVATAS designed as an international, multicentre, randomised trial, which will evaluate stenting of carotid
artery stenosis in patients with cerebrovascular disease.
Centre
requirements: A neurologist or physician with an
interest in stoke; a surgeon with expertise in carotid endarterectomy and an interventionalist with expertise in carotid angiography and
the techniques of angioplasty and stenting.
Inclusion
criteria: Symptomatic atheromatous carotid stenosis, > 50% by
NASCET criteria, suitable for stenting and surgical endarterectomy.
Treatments:
Patients will be randomised in equal proportions
to be treated by carotid endarterectomy or stenting. New design of stents,
filters and protection devices will be incorporated into the study to allow
tracking of new technology if approved by the Steering Committee. Surgery can
be performed with local or general anaesthesia.
Sample
size: N = 1500
patients. Sample size calculations show that the 95% confidence intervals will
be ±
3.0 percentage points for the outcome measure of 30 day stroke, myocardial
infarction and death rate and ± 3.3 percentage points for the outcome measure
of death or disabling stroke during follow-up.
Primary
outcome measure: Long term survival
free of disabling stroke.
Secondary
outcome measures: Any stroke, myocardial
infarction or death within 30 days of treatment, treatment-related cranial
nerve palsy or haematoma. Stenosis (>70%) and occlusion on
ultrasound follow-up. Transient ischaemic attack.
Stroke during follow-up. Further treatment procedure. Quality of life and economic measures.
Stroke
is the major cause of acquired adult physical disability and is responsible for
12% of all deaths in the
Stenting is a new method of treating carotid stenosis, which has evolved from the technique of percutaneous transluminal angioplasty (PTA). Stenting avoids some of the hazards of surgery and has become an established treatment for peripheral and coronary artery stenosis. Stenting is less invasive than carotid endarterectomy and has advantages in terms of patient comfort, because the procedure avoids an incision in the neck, and is usually conducted under local anaesthesia. Hospital stay need only be for 24 hours after treatment if uncomplicated. When given the choice, stenting is preferred by many patients. On the other hand, stenting does not remove atheromatous plaque, has not been shown to prevent stroke and may have an unacceptable incidence of restenosis. We therefore propose a multicentre randomised trial to compare carotid stenting with carotid surgery.
Percutaneous transluminal angioplasty: A number of groups have published series of patients with carotid stenosis treated by PTA. The cumulative total of patients in these series is over 1000, with a reported major complication rate of less than 5% at the time of the procedure.3 These data suggested that carotid PTA has a similar risk to carotid surgery, but the results could not be taken as definitive because none of the data were from randomised trials. We therefore started a randomised trial, known as the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) in l992. We completed randomisation in July 1997.
Results of CAVATAS: 560 patients were
entered, from 24 centres in the
Causes and timing of stroke in CAVATAS: The cause of stroke within 30 days of first treatment in CAVATAS was cerebral infarction in 22 patients in the PTA group and 20 patients in the surgery group. Primary cerebral haemorrhage caused the other three strokes in the PTA group and 2 strokes in the surgery group. All but one stroke was ipsilateral to the randomised artery. Suprisingly, a significant proportion of these treatments related strokes were delayed after the day of treatment. Eight (36%) of the strokes in PTA patients occurred between the second and 21st day after treatment. Delayed stroke was also found in 6 (27%) of the surgical group between the third and 10th day after operation. Delayed stroke may account for the relatively high rate of 30-day morbidity in CAVATAS at 10% compared to 7.5% in ECST and 5.8% in NASCET.
Carotid stenting: Stents suitable for carotid use have only become available recently. The CAVATAS Steering Committee decided to allow the use of stents at the discretion of the interventionist. Stents were used in 55 patients randomised to PTA, usually as a secondary procedure i.e. after initial balloon dilation. The indication for using a stent in these cases was usually an inadequate angiographic result and in some cases stents were deployed because of stroke at the time of full balloon inflation, as a ‘bail-out’ procedure. Only one stroke occurred at the time of stent deployment (1.8%), although there were a small number of delayed strokes after stenting.
The need for a trial of carotid stenting: It would be inappropriate to use the results of CAVATAS to propose the widespread introduction of PTA for the treatment of carotid stenosis as an alternative to surgery, because the 95% confidence interval surrounding the 10% risk of any stroke within 30 days of treatment in the surgical and angioplasty groups is ± 5%. Nevertheless, the results support the need for further randomised studies. The interventional technique used to treat carotid stenosis has evolved over the 7 years since we started CAVATAS, from the use of simple inflatable balloon catheters at the beginning of the trial to the increasing use of stenting towards the end of the trial. Initially stents were used only as a secondary procedure after full balloon inflation for inadequate results or complications of treatment. The desire to prevent these complications and superior early results in stented patients has led to the increasing use of the technique of primary stenting in which the intention is to deploy a stent in every patient before dilation (but after pre-dilatation to allow the atraumatic passage of the stent) of the artery5. Primary stenting is now accepted as best practice5 and has become the radiological technique of choice for carotid stenosis, replacing balloon angioplasty.
Advantages of carotid stenting: The majority of major strokes after carotid PTA are the result of dissection of the carotid artery at the time of balloon inflation with subsequent thrombosis. It is believed that stenting is safer than simple balloon angioplasty because embolisation, dissection and closure of the carotid artery are less likely to occur.6,7 The subgroup analysis of stented patients in CAVATAS is consistent with this suggestion. The adverse consequences of dissection are minimised, because the stent maintains laminar flow across the stenosis and seals the site of dissection, preventing a free intimal flap. In addition, the stent mesh limits the size of any thrombus or atheromatous debris that may be dislodged from the plaque at the time of dilation of the artery. Superior dilation achieved by stenting compared with balloon angioplasty may also reduce the rate of stroke in the early post-treatment period. In the coronary circulation, stenting has been shown to produce superior outcomes compared with balloon angioplasty.8,9 Individual case series suggest that carotid stenting has a similar rate of procedural stroke to that of carotid surgery,6,7 while a recent registry reported a total of 2,048 patients from 24 centres undergoing carotid stenting with a complication rate of stroke and death within 30 days of treatment of 5.8%.10
Disadvantages of carotid stenting: Although acceptable safety at the time of stenting has been suggested by the case series and registry data, stenting has not been subjected to a randomised trial in comparison to conventional surgical treatment and has not been demonstrated to prevent stroke, which is the aim of treatment. Stenting does not remove atheromatous plaque and stents may stimulate neo-intimal hyperplasia. In the long term it is likely that the rate of restenosis will be greater after stenting than after carotid surgery, which could well result in an unacceptable rate of long-term stroke recurrence. There is an important need to establish the efficacy of carotid stenting in comparison to surgery before the technique is widely introduced without adequate trial based evidence.
Antiplatelet therapy: In cardiological practice, ischaemic complications during coronary stenting have been shown to be significantly reduced by using a combination of two antiplatelet agents, ticlopidine and aspirin. In one coronary trial, stent thrombosis was reduced from 3.6% in patients assigned aspirin alone down to 0.5% in patients assigned aspirin and ticlopidine.11 A recently completed trial has shown that similar results with less risk of side effects can be achieved during coronary stenting by using the combination of clopidogrel with aspirin.12 It is likely that this combination would also reduce the risks of stroke during carotid stenting. A pilot study is currently being carried out at one of the centres to establish the safety of the combination of clopidogrel and aspirin given before and for 30 days after carotid stenting. It is likely that this will become standard therapy. Most surgeons currently believe that combination antiplatelet therapy during surgery is hazardous because of excess bleeding.
Economic and quality of life considerations:
Quality of life and general health status were assessed in CAVATAS using the
SF36 and EuroQol EQ-5D questionnaires. These showed a
similar quality of life for patients randomised to either treatment. Operating
and radiology suite costs were similar in a sample of patients at two
To compare the risks, benefits and cost effectiveness of a treatment policy of referral for carotid stenting compared with referral for carotid surgery.
ICSS is an
international, multicentre, randomised, controlled, open, prospective clinical
trial comparing carotid surgery with carotid stenting.
Each centre
must have a neurologist or physician with an interest in stroke who will see
patients prior to randomisation and for follow up. Carotid endarterectomy must
be carried out by designated surgeons with expertise in the operation. Carotid
stenting will be carried out by designated consultant interventionists with
expertise in carotid angiography and the techniques of angioplasty and
stenting. Good collaboration between the neurologists, surgeons and
interventionists is essential and centres should have regular neurovascular
meetings. Attendance at training sessions in carotid stenting provided by
credentialing centres will be required for all interventionists prior to
participation. Participating centres will be required to submit curriculum vitae for all participating
clinicians and an audit of recent carotid surgery and PTA/stenting results. An
accreditation committee will decide if they have appropriate experience and
expertise to join the study. As a guide, surgeons and interventionists will be
expected to show a stroke and death rate within 30 days of treatment,
consistent with the centres in ECST who had an average rate of 7.0% with a 95%
confidence interval of 5.8 to 8.3%.1 Surgeons will be expected to
have performed a minimum of 50 carotid operations with a minimum annual rate of
at least 10 cases per year. Interventionists will similarly be expected to have
performed a minimum of 50 stenting procedures, of which at least 10 should be
in the carotid territory. Centres where there is little or no experience of
carotid stenting may join ICSS for a probationary period in order to gain the
minimum experience of ten carotid stenting procedures required to join the
trial fully. The results in patients randomised during the probationary period
will be analysed separately.
All centres
will have to provide proof of Ethical Committee Approval for the study before
commencing randomisation.
Probationary
centres will be required to fulfil all the other requirements for entry, but
will not have to provide audited data on ten carotid stenting procedures
initially. Probationary centres will randomise patients within the ICSS
protocol between surgery and stenting. Individual interventionists who are not
able to satisfy the credentialing requirements will be identified as
probationary investigators. Stenting procedures carried out during the
probationary period must be proctored by an experienced carotid interventionist,
until the proctor is satisfied that the interventionist(s) at the centre can
satisfactorily carry out procedures unproctored. Probationary
interventionists will become fully enrolled in ICSS when both the
proctor is satisfied that the interventionist can perform procedures
unsupervised and the interventionist has 10 or more successfully completed
cases in the trial, with an acceptable complication rate. When
an investigator has done sufficient successful procedures, the trial office
will get comments from the relevant proctor, and then have any decision to
promote the investigator or centre signed off by the chair of steering
committee.
Proctors for probationary centres will be approved by the accreditation committee in consultation with the probationary centre via the central ICSS office. Probationary centres may suggest an appropriate proctor, but he or she will require prior approval from the accreditation committee, based on review of the proctor’s experience of carotid stenting. It is the responsibility of the probationary interventionist to make contact with an approved ICSS proctor and to ensure a convenient date is organised for the stenting procedure at which the proctor can be present. Copies of the relevant radiology should be available for the proctor for review prior to starting the stenting procedure. This should be done prior to randomisation if there was any doubt about the suitability of the patient for stenting. In the event of a centre requiring proctoring for surgery the same procedure will apply.
It is the responsibility of the probationary interventionist and the proctor in discussion to ensure the lesion is appropriate for treatment (e.g. sufficiently severe), that the patient has received appropriate premedication (e.g. a combination of clopidogrel and aspirin) and that the lesion is suitable for stenting. They should agree the type, range and sizes of equipment required and the probationary interventionist should ensure that this equipment is available to complete the procedure. If any of these conditions are not met, the procedure should be abandoned and if appropriate rescheduled for another occasion.
Catheter or
arch angiography is not required in ICSS prior to randomisation if the centre
does not routinely perform angiography prior to treatment. However, the centre interventionist, the
proctor and the patient should be aware that if preliminary angiography at the
time of planned stenting shows a lesion which is not suitable for stenting, the
procedure should be abandoned and the patient referred for surgery, or
continued medical management. This type
of cross over is envisaged in the trial design.
Where a
centre has an adequately qualified surgeon and interventionist they may
supervise surgeons and interventionists at the same centre whose experience
would not initially qualify them for the trial until they have gained
sufficient experience.
·
Symptomatic, extracranial,
internal or bifurcation, atheromatous carotid artery stenosis that is suitable
for both stenting and surgery and is deemed by the randomising clinician to
require treatment.
·
The severity of the stenosis
of the randomised artery should be at least 50% (as measured by NASCET method
or non-invasive equivalent).
·
Symptoms must have occurred in
the 12 months before randomisation. It is recommended that the time between
symptoms and randomisation should be less than 6 months, but patients with
symptoms occurring between 6 and 12 months may be included if the randomising
physician considers treatment indicated.
·
The patient must be clinically
stable following their most recent symptoms attributable to the stenotic vessel.
·
Patients must be willing to
have either treatment, be able to provide informed consent, and be willing to
participate in follow up.
·
Patients must be able to
undergo their allocated treatment as soon as possible after randomisation.
·
Any age greater than 40 may be
included. There is no upper age limit.
·
Patients should only be
randomised if the investigator is uncertain which of the two treatments is best
for that patient at that time.
· Patients refusing either treatment.
·
Patients unable or unwilling
to give informed consent.
· Patients unwilling or unable to participate in follow up for whatever reason.
· Patients who have had a major stroke with no useful recovery of function within the territory of the treatable artery.
· Patients with a stenosis that is known to be unsuitable for stenting prior to randomisation because of one or more of:
- Tortuous anatomy proximal or distal to the stenosis
- Presence of visible thrombus
- Proximal common carotid artery stenotic disease
- Pseudoocclusion (‘string sign’).
· Patients not suitable for surgery due to anatomical factors e.g. high stenosis, rigid neck.
· Patients in whom it is planned to carry out coronary artery bypass grafting or other major surgery within 1month of carotid stenting or endarterectomy.
· Carotid stenosis caused by non-atherosclerotic disease e.g. dissection, fibromuscular disease or neck radiotherapy.
· Previous carotid endarterectomy or stenting in the randomised artery.
· Patients in who common carotid artery surgery is planned.
· Patients medically not fit for surgery.
· Patients who have a life expectancy of less than two years due to a pre-existing condition, e.g. cancer.
An anonymised log will be kept of patients undergoing treatment for carotid stenosis by the trial investigators but not randomised at the participating centres. Patients undergoing stenting but not randomised should also be included on a suitable registry, such as EUROCAST.
Written witnessed, informed consent will be obtained from all patients and a copy must be retained by the randomising centre. All patients will be provided with a written explanation of the study.
Randomisation
will be by a telephone call or fax to a computerised service provided by the
Oxford Clinical Trials Service Unit. Randomisation will be stratified by centre
with minimisation of the main risk factors and balanced between the arms. Patients
who need treatment of both carotid arteries will only be randomised for the
carotid artery to be treated first. Patients can only be randomised once.
The following investigations are required: Routine haematology (FBC,
platelets), blood biochemistry (renal function, blood sugar, cholesterol),
chest x-ray, ECG, brain CT or MRI scans. The brain scan is required to exclude
other pathology, to identify existing infarcts and to provide a baseline
reference against which any subsequent infarction or haemorrhage can be
assessed. Copies of the CT or MRI scans should be sent to the ICSS office
Mandatory investigation is required for entry into the study to confirm
the presence and severity of the ipsilateral stenosis and to assess contralateral carotid disease. The following are
acceptable:
1.
Arch arteriogram showing both
carotid bifurcations,
2.
Selective catheter carotid
angiography showing the randomised carotid artery with non-invasive
investigation of the contralateral carotid
bifurcation.
3.
Bilateral magnetic resonance
carotid angiograms together with a concordant ultrasound scan.
4.
Bilateral spiral CT angiograms
together with a concordant ultrasound scan.
5.
Bilateral duplex and Doppler
ultrasound scan, only if this is standard practice to treat on the basis of
ultrasound alone in individual centres and the centre has been able to provide
proof of the reliability of their ultrasonographic
imaging through clinical audit.
The following data from the pre-randomisation imaging will be sent to the Central Office for review:
1) A copy of the written reports of the studies.
2) A film copy of the view of the vessel to be treated showing the stenosis at its most severe.
3) A film copy of the view of the contralateral vessel showing any stenosis at its most severe.
4) Velocity data from the ultrasound examination.
Patients who are randomised to stenting after ultrasound or other non-invasive investigation, in which subsequent angiography, prior to stenting, reveals one or more exclusion criteria should be treated by surgery, if appropriate, or medical care only if surgery is not appropriate (e.g. because the stenosis is less than 50%). These patients will continue follow up in the trial and will be analysed on an intention to treat basis. A similar approach should be taken to patients randomised to surgery in whom contraindications to surgery emerge after randomisation.
Ultrasound study of the carotid artery to be treated will be performed
at or before randomisation, at one month after treatment and then annually
after randomisation. The following information is required for each study: Peak
systolic velocity of internal carotid artery (PSV ICA), end diastolic velocity
of internal carotid artery (EDV ICA), peak systolic velocity of common carotid
artery (PSV CCA). The accuracy of individual ultrasound laboratories will be
audited by comparing the pretreatment ultrasound
examination against catheter angiography films, which will be available in
patients randomised after angiography and in all the patients treated by
stenting.
Baseline data collected at randomisation will include demographic data;
existing medical risk factors; neurological symptoms including an assessment of
disability using the Modified Rankin Scale (see Appendix I); current
antiplatelet therapy and blood pressure. Films and/or reports of
pre-randomisation imaging as detailed above and in all cases the results of
Doppler ultrasound as detailed below are required to allow assessment of any
subsequent stenosis.
Patients will be seen by the study neurologist or physician interested
in stroke prior to randomisation to confirm suitability for the study.
Stenting will be carried out as soon as possible after randomisation using percutaneous transluminal interventional techniques from the femoral, brachial or common carotid artery by a designated interventional consultant using an appropriate stent. A cerebral protection system should be used whenever the operator thinks one can be safely deployed. Stents and other devices used in the trial must be CE marked and approved by the Steering Committee. Pre-medication will be discretionary. The combination of aspirin and clopidogrel is recommended as the antiplatelet regime of choice to cover the period of stenting and for a minimum of 4 weeks afterwards. Intra procedural heparin is mandatory at a dose determined by the operator, post procedural heparin may be given according to clinical requirements. Patients should be monitored for changes in their neurological status and heart rate throughout the procedure. If femoral or brachial access is being used a long sheath introducer or a guiding catheter is placed in the common carotid artery allowing pre-dilation and stent placement under direct arteriographic imaging. Atropine, or a similar agent, must be administered prior to stent deployment to counteract any effects on the carotid artery baroreceptors, which could lead to severe bradycardia and / or asystole. Virtually all patients will require pre-dilatation of the stenosis by balloon angioplasty prior to stent deployment. This will minimise the embolic load caused by passage of the endoluminal stent through the stenosis. The size of the pre-dilatation balloon will be determined by the size of the delivery system being used. Further balloon dilation of the stent will usually be required to ensure apposition of the stent against the arterial wall. Angiographic images showing the stenosis at its most severe prior to stenting and the same view and any other view that demonstrates the maximum residual stenosis after stenting must be sent to the Central Office. Details of the procedure, including all peri-procedural complications, drug therapy and devices used in the procedure, must be reported and the stenting and cerebral protection technical data sheet returned to the trial Central Office.
Endarterectomy is to be done as soon as possible after randomisation by a designated consultant surgeon who has been approved by the Credentials Committee. It is to be carried out using whichever procedures are standard at the individual centre, including the use of local or general anaesthesia, shunts or patches as required by the operating surgeon. Standard or eversion endarterectomy may be performed.
Reporting of suspected problems with surgical or stenting techniques at
individual centres
If the local investigator, or other member of the team, at a trial centre has concern about the outcome of their trial procedures, they should inform the ICSS trial office, which will organise a blinded assessment of the relevant outcome events. This will be submitted by the central office to the chairman of the data monitoring committee who may recommend further action, such as suspending randomisation at the centre. Similarly, the database manager at the trial office will monitor outcome events and if there are two consecutive deaths or three consecutive major events at a single centre within 30 days of treatment in the same arm of the study, then assessment of the events will be triggered. A cumulative major event or death rate of more than 10% over 20 cases would also trigger careful assessment of the relevant outcome events.
All
patients will receive best medical care including antiplatelet therapy or
anticoagulation (when appropriate) and control of medical risk factors such as
hypertension, smoking and hyperlipidaemia before
treatment and throughout the period of follow up.
Therapy to prevent thrombosis during or soon after surgery or stenting will be prescribed according to standard practice in each centre. This may include heparin, dextran, aspirin, dipyridamole, ticlopidine, clopidogrel, or a combination of aspirin and another antiplatelet agent. Glycoprotein IIb/IIIa antiplatelet receptor antagonists will not be used routinely.
Patients will be followed up by a neurologist or a physician interested in stroke at the participating centres at 30 days after treatment, 6 months after randomisation and then annually after randomisation. All post-procedural complications occurring within thirty days after the procedure will be reported to the central office at the 30 day follow up. At each visit, levels of stroke related disability will be assessed using the modified Rankin Scale (see Appendix 1) and any relevant outcome events will be notified to the Central Office. A Doppler ultrasound will be used to measure carotid arterial diameter to assess patency at one month after treatment and then annually after randomisation. In addition, ultrasound re-examination and CT or MRI scan should be performed in-patients who have any transient ischaemic events and / or stroke during follow up.
The planned sample size is 1500. We do not anticipate any large difference in the principal outcome between surgery and stenting. We propose to estimate this difference and present a confidence interval for difference in 30-day death, stroke or myocardial infarction and for three-year survival free of disabling stroke or death. For 1500 patients, the 95% confidence interval will be the observed difference ± 3.0 percentage points for the outcome measure of 30 day stroke, myocardial infarction and death rate and ± 3.3 percentage points for the outcome measure of death or disabling stroke over three years follow up. However, the trial will have the power to detect major differences in the risks of the two procedures, for example if stenting proves to be much riskier than surgery or associated with more symptomatic restenosis. The difference detectable with power 80% are 4.7 for 30 day outcome and 5.1 percentage points for survival free of disabling stroke. Similar differences are detectable for secondary outcomes. We expect to achieve this recruitment within 6 years.
· What is the difference in the long-term rate of fatal or disabling stroke in any territory of patients with severe symptomatic stenosis after randomisation to a policy of carotid stenting compared to surgery?
· What are the differences in mortality and morbidity within 30 days of carotid stenting compared to surgery?
· What is the rate of symptomatic and asymptomatic restenosis after carotid stenting compared to surgery?
· What are the differences in the rate of ipsilateral stroke during follow-up after carotid stenting compared to surgery?
· What is the cost-effectiveness of carotid stenting compared to surgery?
(see Appendix 1)
· Any stroke or death.
· Transient ischaemic attack.
· Myocardial infarction within 30 days of treatment.
· Cranial nerve palsy within 30 days of treatment.
· Haematoma caused by treatment requiring surgery, transfusion or prolonging hospital stay.
· Stenosis greater than 70% or occlusion during follow up.
· Further treatment of the randomised artery by interventional radiology techniques or surgery after the initial attempt.
·
Quality of life, health status and Health
Service costs (see paragraph below).
Outcome
events will be documented in detail by the investigating centre, censored after
receipt at the central office to remove clues as to the treatment received, and
then adjudicated by an independent neurologist. Patients suffering
stroke should have a CT or MRI brain scan as soon as possible after the event.
A film copy of this, together with a film copy of the pre-randomisation scan
(if done) should be submitted together with a report of the event. The event
report should include copies of discharge summaries; death certificates and
post mortem results if relevant. Deaths of
Carotid stenting is a new procedure, while the techniques of carotid surgery are well established. It is likely that there will be a learning curve for carotid stenting and the results may improve with experience during the trial. However, we believe it is better that carotid stenting should be performed as part of a randomised clinical trial at this stage of its development, because this will ensure careful assessment and follow up of all patients treated in the trial and supervision from the Data Monitoring and Ethics Committee ensures that continuing treatment with the new technique remains ethical. The influence of the early part of the learning curve for carotid stenting will be limited by careful training of individual interventionists. The total experience of carotid PTA and stenting of individual interventionists will be recorded prior to entry into the trial. This will allow the average duration of the learning curve to be analysed, taking into account the current experience of the individual interventionists. This information may have implications for interpretation of the results of the trial and for the future training and supervision of the procedure. Similarly, there may be improvements in individual surgical or anaesthetic techniques during the trial.
The field of carotid stenting is an area of fast changing technology. The
protocol does not at present specify the type or manufacturer of the stents or
protection devices to be used, but devices to be used in the trial will be CE
marked and approved by the Steering Committee who will expect a peer reviewed
report of device safety. More than one device may be recommended to allow the
interventionist to tailor the choice of stent to the individual stenosis and to
use new designs of stent or protection devices if appropriate. The protocol
will not specify the technique to be used during carotid surgery. Decisions
about the use of shunts or specific suture materials will be left to the individual
surgeon. Local or general anaesthesia will be allowed in both arms. Technical
details of surgical and stenting technique, including the manufacturer and type
of stent used, the use of local or general anaesthesia, and the use of antithrombotic agents, will be recorded. The analysis will
include a subgroup comparison of different techniques in both arms and the data
will be presented to the DMC meetings to ensure that no one technique is
significantly inferior to another. Randomisation will use a computer programme
to minimise variation between centres and over time, so that equal numbers of
patients will be entered into the stenting and surgery arms before and after
any change in practice.
If the trial confirms the hypothesis that carotid stenting and surgery are equivalent in terms of the major risks of stroke and death, then the choice between the two procedures will be determined primarily by differences between the two procedures in other outcomes e.g. the disadvantage of a scar or cranial nerve palsy, or the effects of surgery on health related quality of life. If these differences are minor, the choice between the procedures will be made primarily on economic grounds. The effects of cranial nerve palsy may be detected by a minor increase in the disability score, but it is not easy to assess the effect of these outcomes during follow up on clinical examination alone. Quality of life and health status will therefore be assessed using the EuroQol (EQ5D) questionnaire14 to compare patients’ feeling of well-being, health and quality of life before and after stenting or surgery at one month, six months and annual follow up. The results will be analysed blind to treatment arm. The first questionnaire will be completed at the time of randomisation and subsequent questionnaires at each follow-up visit. The investigator performing randomisation or follow-up should ensure the patient completes the EQ5D at the same time. The English language version of the EQ5D has been modified to record the date on which it is completed and the patients trial number. Those centres using versions in other languages should also record the date and trial number on each completed form. If patients are too disabled to complete the questionnaires themselves, the patient’s carer may complete them. The EQ5D should be returned to the central office with the other trial forms.
Information on hospital resource use during the treatment and follow up, including the type and manufacturer of the devices employed in carotid stenting procedures, will be collected to measure treatment costs and estimate the costs of stroke and any consequences of restenosis (e.g. retreatment) during follow up. The costs of stroke caused by treatment are a major component of the total cost of treatment, and therefore have a major influence on cost effectiveness. As the additional length of stay in hospital resulting from stroke largely drives these costs, the prospective collection of length of stay data will be designed to capture the stroke-related data in addition to direct operative stay. The economic evaluation will address cost-effectiveness and cost-utility (cost per QALY). The latter will be estimated from patients’ responses to the EuroQol (EQ-5D) questionnaires using the York MVH tariff. Uncertainty regarding specific parameters within the analysis will be subjected to a sensitivity analysis, and uncertainty around the point estimate of the cost utility ratio will be represented using cost-effectiveness acceptability curves.
Patency of the carotid artery will be monitored by Doppler ultrasound at a minimum of 30 days after treatment and then annually after randomisation. Restenosis should only be treated by further angioplasty or surgery if the patient has relevant new symptoms. Restenosis is usually the result of smooth muscle hypertrophy or neo-intimal hyperplasia, rather than recurrence of atherosclerosis and hence may not cause embolic stroke. Asymptomatic restenosis will not be an indication to retreat the lesion because the risk of disabling symptoms after restenosis is not known.
Crossovers before any attempt to treat the randomised artery by the allocated treatment will be avoided unless clinically essential, because the trial data will be analysed by intention to treat. Patients who are randomised to stenting after ultrasound or other non-invasive investigation, in whom subsequent angiography prior to stenting, reveals one or more exclusion criteria should be treated by surgery, if appropriate, or medical care only if surgery is not appropriate (e.g. because the stenosis is less than 50%). These patients will continue follow up in the trial and will be analysed on an intention to treat basis. A similar approach should be taken to patients randomised to surgery in whom contraindications to surgery emerge after randomisation. Patient refusal of the treatment to which they are randomised can be minimised by careful consent. Patients requiring re-treatment because of further symptoms should be re-treated with whichever treatment is most appropriate. This is also the case if the non-randomised carotid artery requires treatment. Patients in whom an attempt at stenting fails may proceed to early surgery if appropriate and vice versa.
The data will be analysed by intention to treat using standard statistical tests by the trial statistician. The analyses will compare the treatment groups with respect to the length of time before treatment failure (i.e. occurrence of an outcome event) by means of the Mantel-Haenszel chi-squared test and Kaplan-Meier survival curves. Secondary analysis will compare the proportions of outcome events within 30 days of treatment. All analyses will be adjusted for centre and predetermined risk factors. Subgroup analyses will examine risk factors for major outcome events. The results of any interim data analysis will remain confidential to the trial statistician and Data Monitoring Committee until after completion or early discontinuation of the trial. Investigators and the Steering Committee will remain blind until such point.
Publication of the results of ICSS will be prepared by the Central Office and circulated to participating centres for comment prior to submission of the manuscript for publication on behalf of all the ICSS collaborators.
Multicentre
Research Ethics Committee approval will be sought in the
The safety aspects of the trial will be overseen by a Data Monitoring Committee consisting of an independent neurologist, medical statistician surgeon and interventionist. The progress of the study will be assessed at regular intervals determined by the Data Monitoring Committee. During the period of intake to the study, interim analyses of mortality and of any other information that is available on major endpoints (including serious adverse events believed to be due to treatment) will be supplied, in strict confidence, to the chairman of the Data Monitoring Committee, along with any other analyses that the Committee may request. In the light of these analyses, the Data Monitoring Committee will advise the chairman of the Steering Committee if, in their view, the randomised comparisons in ICSS have provided both (i) "proof beyond reasonable doubt" that for all, or for some, specific types of patients, one particular treatment is clearly indicated or clearly contraindicated in terms of a net difference in outcome, and (ii) evidence that might reasonably be expected to influence materially patient management. Appropriate criteria of proof beyond reasonable doubt cannot be specified precisely, but a difference of at least 3 standard deviations in an interim analysis of a major endpoint may be needed to justify halting, or modifying, the study prematurely. This criterion has the practical advantage that the number of interim analyses is of little importance.
Steering Committee Committee, consisting of individuals participating in and independent of the trial with experience in stroke medicine, neurology, vascular surgery, vascular radiology, interventional neuroradiology, health economics, clinical trials and statistics, will oversee the management of the trial.
The study
will be organised on behalf of the collaborators by the central office, located
at the
For the time being, the Lead Institution
(The Institute of Neurology,
ICSS is an academic trial performed as a
collaborative effort for the benefit of patients, and is not performed for, or
on behalf of an industry sponsor. The trial compares two existing forms of
treatment currently used in many hospitals. The various devices approved for
use in the trial are not investigational devices and are required by the
protocol to be marketed and already in use in the carotid artery as recognised
by the CE mark. Hence, the trial is not an industry sponsored test of a new
treatment with unknown hazards. The trial protocol anticipates that some
patients may be harmed inadvertently as a result of treatment in the trial.
Indeed, the determination of the rate of these adverse outcome events is a
major aim of the trial. However, we believe that the risks of these adverse
events will be outweighed by the benefits of treatment in either arm of the
trial. The trial protocol does not subject patients to hazards that the patient
would not have encountered if they had received the trial treatments outside
the context of the trial in routine practice. Hence, the organisers of the
trial cannot take responsibility for any harm occurring to patients as a result
of partaking in the trial. Individual investigators and hospitals are required
to take responsibility for the occurrence of any adverse events in the same way
as they would do if the treatments were performed outside the trial.
The trial website contains updated
information about the trial together with downloadable copies of the protocol,
trial data collection forms, newsletters and contact information. The names of
the collaborating centres will be included on the website. The website address
is www.cavatas.com and all the pages are accessible to the public, patients and
collaborators alike without a password. At present, the data collection forms
cannot be completed on line.
1. European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of
endarterectomy for recently symptomatic carotid stenosis: final results of the
MRC European Carotid Surgery Trial(ECST). Lancet1998. 351:1379-1387.
2. North
American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of
carotid
endarterectomy in-patients with symptomatic, moderate or
severe stenosis. N-Engl-J-Med.
1998;339:1415-25.
3. Brown
MM. Angioplasty for stroke prevention. In: Ginsberg L. Bogousslavsky
J, Eds.
Cerebrovascular disease: pathophysiology,
diagnosis and management.
4. CAVATAS Investigators. Endovascular
versus surgical treatment in patients with carotid stenosis in the Carotid and
Vertebral Artery Transluminal Angioplasty Study: a randomised trial. Lancet: 2001, 357: 1729-1737.
5 Coward L, Featherstone RL, Brown MM.
Percutaneous transluminal angioplasty and stenting for carotid artery stenosis.
(Cochrane Review). In: The Cochrane Library, Issue 4, 2002.
6. Diethrich EB, Ndiaye M, Reid DB.
Stenting in the carotid artery: initial experience in 110
patients. Journal of Endovascular
Surgery. 1996;
7. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial
carotid arteries.
Circulation. 1997;95:376-381.
8. Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent
implantation with balloon angioplasty in-patients with
coronary artery disease. Benestent Study
Group. NEJM.
1994;331:489-495.
9. Fischman DL,
and balloon angioplasty in the treatment of coronary artery
disease. Benestent Study Group.
NEJM. 1994;331:496-501.
10. Wholey MH, Wholey M, Bergeron P et al. Current global status of
carotid artery stent placement. Cathet. Cardiovasc.
Diagn.
1998;44:1-6.
11. Leon-MB,
Baim DS, Popma JJ et al. A clinical
trial comparing three antithrombotic-drugs
regimens after coronary-artery
stenting. N-Engl-J-Med.
1998;339:1665-71.
12. Bertrand ME, Rupprecht HJ, Urban P,
Gershlick AH,Investigators
for the CLASSICS Double-Blind Study of the
Safety of Clopidogrel With and Without a Loading Dose in Combination With
Aspirin Compared With Ticlopidine in Combination With Aspirin After Coronary
Stenting: The Clopidogrel Aspirin Stent International Cooperative Study
(CLASSICS Circulation. 2000:102;624-629
13. Davies A., Buxton M, Brown MM et al. The cost effectiveness of
percutaneous transluminal angioplasty compared to carotid endarterectomy for
the treatment of severe carotid artery stenosis. Paper to be submitted in
parallel with reference.4
14. Brazier
J, Usherwood T, Harper R, Thomas K. Deriving a
preference based single index from the UK SF-36 health survey. J Clin
Epid. 1998;51; 1115-18.
· Transient ischaemic attack (TIA): An acute disturbance of focal neurological function with symptoms lasting less than 24 hours attributed to cerebrovascular disease.
· Transient monocular blindness (Amaurosis fugax): Acute total or partial loss of vision in one eye with recovery within 24 hours attributed to vascular disease. This will be included as a variety of TIA.
·
Stroke: An acute disturbance of focal
neurological function with symptoms lasting more than 24 hours resulting from
intracranial vascular disturbance. It must be established whether the cause is
infarction or haemorrhage (primary intracranial or subarachnoid).
Visual loss resulting from embolic or haemodynamic
retinal ischaemia lasting more than 24 hours will be
included within the category of stroke.
· Myocardial Infarction: Two of the following have to be documented: specific cardiac enzymes more than twice the upper limit of normal, a history of chest discomfort for at least half an hour, or the development of specific abnormalities (e.g. Q waves) on a standard 12 lead electrocardiogram.
·
Cranial Nerve Palsy: weakness or
sensory impairment in the distribution of one of the cranial nerves attributed
to treatment.
·
Haematoma: bleeding attributed to the
treatment of carotid narrowing requiring new surgery, transfusion or prolonging
hospital stay.
· Disabling Outcome Events: disability after stroke and cranial nerve palsy will be assessed using the Modified Rankin scale (defined below). Outcome events will be classified as disabling if the Rankin score is 3 or greater for more than 30 days after onset. The Rankin scale will be recorded at one and six months after treatment and then at annual follow up. Investigators will be asked to estimate the Rankin scale at one and six months after onset of new stroke when they see the patient more than 6 months after onset of stroke.
· Recovered strokes: in patients who make a full recovery from stroke or other outcome events, the duration from onset to full recovery will be recorded in days.
·
Modified
Rankin Scale
The
following modified Rankin scale will be used to assess residual disability from
stroke at randomisation to establish a baseline level of disability and at
every follow up visit to assess the severity of any subsequent stroke:
|
0 |
Asymptomatic. |
|
1 |
Non-disabling
symptoms which do not interfere with lifestyle. |
|
2 |
Minor disability - symptoms which lead to some
restriction of lifestyle but do not interfere with the patient’s capacity to
look after themselves. |
|
3 |
Moderate disability – symptoms which significantly interfere with lifestyle or prevent totally independent existence, but able to walk
without assistance. |
|
4 |
Moderately severe disability – symptoms which clearly prevent independent existence, unable to walk without assistance, although the patient does not need constant attention day and night. |
|
5 |
Severely disabled – totally dependent requiring constant attention day and night. |
|
6 |
Dead. |
Independent Chairman Dr. John Bamford, Consultant Neurologist and Stroke Physician.
Principal investigator: Professor Martin M. Brown, Professor
of Stroke Medicine,
Vascular Surgery: Professor Andrew Bradbury, Professor of Vascular Surgery,
Mr
Jonathan Beard, Consultant Vascular Surgeon,
Miss Alison Halliday, Consultant Vascular Surgeon and Principal Investigator, Asymptomatic Carotid Surgery Trial.
Vascular Radiology: Dr Peter Gaines, Consultant
Vascular Interventionist,
Cardiology Dr
Iqbal Malik, S Mary’s Hospital London
Neuroradiology: Dr Andy Clifton, Consultant Neurointerventionist, Atkinson Morley's Hospital
Neurology: Dr Graham Venables, Consultant Neurologist, Royal Hallamshire
Hospital,
Radiologist
advising: Dr Paul Sidhu,
on Ultrasound Studies
Epidemiology: Dr Ale Algra,
Health Economics: Professor AJ McGuire, Professor
of Health Economics,
Statistics: Professor Martin Bland, Professor of
Health Statistics, University of
Dr.
Sue Richards, Statistician, Clinical Trial Service Unit,
Representatives of other Professor Werner Hacke, Principal Investigator of SPACE,
ongoing trials
Professor Jean-Louis MAS, Principal Investigator EVA-3S,
Hôpital Sainte-Anne, Paris
Dr José M. Ferro, MD, PhD Serviço de Neurologia
Hospital de
Dr Dafydd Thomas, St Mary’s
Hospital London, UK
Professor
C. Warlow, Chairman,
Professor
Rory Collins, Clinical Trial Service Unit,
Interventionist
Dr Andrew Molyneux, Consultant Neurointerventionist, Radcliffe Infirmary,
Surgeon
Mr Ross Naylor (Senior Lecturer in Surgery,
Dr
H Watt (Statastician, The
The Central Trial Office at the Institute of
Neurology is manned by a Trial Manager, Data Manager, Clinical Research Fellow
and Research Nurse – Box 6 The National Hospital Queen Square London WC1N 3BG.
Tel +44 (0)207 676 2194
.
It has been prospectively
agreed that ICSS, the stent-protected percutaneous angioplasty vs carotid endarterectomy study (SPACE) (carried out in
Germany), and the endarterectomy versus
angioplasty in patients with severe symptomatic carotid stenosis study (EVA-3S)
(carried out in France), will combine their results after completion of initial
randomisation and follow up, to conduct a combined European meta-analysis of
the data. The data will be combined and analysed at the
Baseline data collected in all
3 studies at randomisation will include age; gender; existing medical risk
factors; current systolic blood pressure; symptoms prior to randomisation
(hemisphere or ocular transient ischaemic attack, hemisphere or ocular stroke);
severity of ipsilateral stenosis; presence or absence of contralateral
occlusion and date of randomisation.
Doppler ultrasound will be
carried out at the time of randomisation and then annually after randomisation
to assess restenosis rates. Peak systolic velocity of common carotid artery
(PSV CCA), peak systolic velocity of internal carotid artery (PSV ICA), and end
diastolic velocity of internal carotid artery (EDV ICA) will be recorded in m/s
to facilitate central analysis.
The following outcome events
and date of onset will be recorded in all three trials:
· Any stroke or death.
· Transient ischaemic attack
· Myocardial infarction within 30 days of treatment.
· Cranial nerve palsy within 30 days of treatment.
· Haematoma caused by treatment requiring surgery or transfusion.
· Ipsilateral occlusion or stenosis greater than 70% during follow up.
· Further treatment of the randomised artery by interventional radiology techniques or surgery after the initial attempt.
·
Duration of treatment related hospital stay.
The severity of neurological outcome events will be assessed by duration of symptoms and effect on the Modified Rankin Scale, using the definitions in Appendix I of the ICSS protocol (see above).
Professor Martin M. Brown
Principal Investigator
The
Queen Square
Tel: +44 (0)20 7829 8753
e-mail: m.brown@ion.ucl.ac.uk
www.cavatas.com