Silk Road Medical First in Man Study - Neuroprotection During Carotid Stenting and Angioplasty
Silk Road Medical First in Man Study - Neuroprotection During Carotid Stenting and Angioplasty
Cerebral embolization during carotid artery stenting (CAS) can often precipitate severe
 adverse neurological effects. Most major clinical studies of CAS have used distal filters for
 cerebral protection and have compared the neurologic complication rates with those of carotid
 endarterectomy (CEA). Many currently available embolic protection devices, however, have
 limited efficacy in capturing microembolic debris that is liberated during stenting,
 pre-dilatation and post-dilatation. Distal protection systems are furthermore limited by the
 need to cross the lesion prior to deployment. Some studies have shown a relatively high
 incidence of cerebral infarction even when distal protection devices are employed.

 Cerebral protection with carotid flow reversal is a method that was developed by Parodi, et
 al., as an alternative to the use of distal protection devices. While novel in its approach,
 this method too has its limitations. Criado, et al., developed a derivative technique that
 employs carotid flow reversal prior to traversing the stenosis and can be accomplished by
 directly accessing carotid anatomy without the use of the transfemoral approach. Major
 benefits to this method include the ability to perform the procedure on patients with severe
 carotid tortuosity and difficult aortic arch anatomy.
Carotid artery disease is known to increase the risk of neurologic consequences such as
 transient ischemic attacks (TIA), ischemic stroke, or death due to the release of embolic
 particles in the vessels supplying the brain. Two principal treatments, carotid
 endarterectomy (CEA), and carotid artery stenting (CAS), are used to treat this disease.
 Embolic protection devices, both distal filters and occlusive devices, are employed during
 the CAS procedure to reduce the risk of carotid plaque embolus secondary to instrumentation
 during carotid intervention. Existing embolic protection devices are placed using a
 transfemoral approach and thus have potential for particle embolization while crossing the
 aortic arch, supraaortic trunk and the carotid lesion before cerebral protection is in place.
 Other limitations of these devices include the potential for carotid intimal injury,
 dissection or spasm during deployment, and release of emboli during retrieval.

 Noting that carotid embolization remains the "Achilles heel" of carotid artery stenting, an
 alternative approach to embolic protection was developed by Juan Parodi. The system works by
 balloon occlusion of the common carotid artery and external carotid artery. An arteriovenous
 fistula is created with sheaths and catheters and provides retrograde (reverse) blood flow
 from the internal carotid artery (ICA) and the common carotid artery (CCA) to the femoral
 vein.

 Embolic particles released during CAS pass retrograde through a catheter into a 180 micron
 filter before the blood re-enters the venous system. (Parodi, Ferreira et al. 2005) A
 variation of the reverse flow approach utilizing a surgical, transcervical approach to the
 carotid artery was developed to address challenges and risks associated with the placement
 and use of existing embolic protection devices. Criado et al. (2004) describe the use of flow
 reversal during CAS via a transcervical surgical cutdown, access and proximal occlusion of
 the CCA and establishment of a carotid artery - internal jugular (IJ) vein fistula. (Criado,
 Doblas et al. 2004).

 A difference between the transfemoral-based Parodi approach and the transcervical-based
 Criado approach is the removal by Criado of the ECA occlusion step. In the Criado approach,
 the procedure is designed such that the flow is reversed in both the internal and the
 external carotid arteries, whereas in the Parodi procedure, flow reversal occurs only in the
 ICA. Another difference in the Criado system is the shorter length and larger diameter tubing
 afforded by the transcervical approach. The rate of flow reversal enabled by the Criado
 arteriovenous shunt is higher and is designed to overcome the potential for antegrade flow
 from the ECA to the ICA.

 However, as reported by both Parodi and Criado, active aspiration is often utilized during
 critical periods of the procedure, to guarantee robust reversal of flow in the ICA.

 Similarly in 2004, Chang, et al., reported the use of a direct transcervical approach through
 a 2cm incision at the base of the neck in 21 CAS patients with a 0% technical failure rate
 and a 0% thirty-day combined stroke or mortality rate. A similar approach of direct access to
 the low common carotid artery and the creation of a shunt to the internal jugular was used
 with carotid occlusion leading to a state of flow reversal. In some cases in this series, a
 balloon was placed in the external carotid artery. (Chang et al, 2004) Subsequently, Criado
 et al reported in the Journal of Vascular Surgery in 2004 on a series of fifty patients who
 underwent carotid artery stenting via this transcervical approach. Using the technique
 described above, flow was reversed in the ICA by occluding the CCA and establishing a
 carotid-jugular vein fistula. There was technical success in all 50 procedures and no strokes
 or deaths occurred. The procedure was tolerated by all but two (4%) of patients.
 Complications included major and minor carotid artery dissections, which resolved after stent
 placement. Two transient ischemic attacks (TIA) occurred, one in a patient in whom flow
 reversal was not successful, and one patient with a contralateral ICA occlusion who suffered
 a contralateral TIA.(Criado, Doblas et al. 2004).

 Criado et al. further report in the Journal of Vascular Surgery in 2004 on a series of 10
 awake patients undergoing transcervical carotid artery stenting with flow reversal.
 Procedural success was achieved in all 10 cases and flow reversal was well tolerated.
 Cerebral oxygenation during ICA flow reversal was comparable to that during CCA occlusion.
 ICA angioplasty balloon inflation produced a decrease in SVO2 significantly greater than that
 occurring during ICA flow reversal. (Criado, Doblas et al. 2004) Finally, Criado et al report
 on the perioperative and 3 year follow up results of 103 consecutive carotid artery stenting
 procedures done with a transcervical approach using carotid flow reversal for cerebral
 protection performed over a 28 month period in 97 patients. Technical success was achieved in
 100 cases (97%). No major strokes or deaths occurred. Three awake patients (4%) did not
 tolerate flow reversal and complications included one ipsilateral TIA, one contralateral TIA,
 and two minor strokes. There were two wound complications and one major arterial
 complication. Mean flow reversal time was 21 minutes. At 40 months, the stent patency rate on
 an intention-to-treat basis was 95%, and the stroke-free survival was 91%. (Criado,
 Fontcuberta et al. 2007).

 In 2006, Ribo and colleagues monitored transcranial doppler (TCD) as part of their standard
 carotid practice where 23 of 65 patients underwent transcervical carotid stenting using
 Criado's technique. Mean reversal time was about 15 minutes and well tolerated. TCD
 monitoring showed an absence of air/solid emboli during stent deployment and angioplasty
 confirming the presence of reverse flow. Baseline middle cerebral artery (MCA) flow by TCD of
 47 cm/sec was substantially decreased with clamping of the common carotid (representing
 reversal of internal carotid flow). Initial mean antegrade MCA velocity of 30 cm/sec was
 present post clamping suggesting that there was adequate hemispheric blood flow to be
 clinically tolerated (Ribo et al. 2006).

 Silk Road Medical has developed a system of sheaths, shunts and flow regulators, called the
 SRM Embolic Protection System, to apply the demonstrated benefits of the Criado and Chang
 approaches and improve further on ease of use and effectiveness. Silk Road Medical has
 provided an arteriovenous shunt with the ability to regulate from a low, baseline flow to a
 higher flow rate. This is accomplished by modulating the flow resistance of a shunt line
 which connects an arterial and a venous sheath. Because of potential patient intolerance to
 long periods of high reverse flow, the flow controller enables the user the set the shunt
 high flow only during periods of the procedure which are high risk for embolic debris
 (angiography, angioplasty, stent placement). This system eliminates the need for an active
 aspiration step, and theoretically enables the user to balance patient tolerance needs with
 optimal embolic protection.

 The conclusion from the series of above literature is that transcervical CAS with carotid
 flow reversal can be accomplished with a high rate of technical success, a very low rate of
 major adverse events, and an excellent 3 year stroke free survival and stent patency rate.
 The purpose of this initial investigation is to determine if the SRM Embolic Protection
 System enables flow reversal of the carotid artery, is compatible with the techniques,
 devices and equipment used during a carotid artery stenting CAS procedure, and does not
 present any additional safety risks to the patient.
Inclusion Criteria:

 -  Subject must be > 21 years of age.

 -  Subject has the ability to understand and cooperate with study procedures and agrees
 to return for all required follow-up visits, tests and exams.

 -  Subjects taking warfarin may be included if their dosage is reduced before the
 procedure to result in an International Normalized Ratio (INR) of 1.5 or less.
 Warfarin may be restarted to therapeutic dose after the procedure.

 -  The subject must sign a written informed consent prior to the procedure, using a form
 that is approved by the local medical ethics committee (EC).

 -  The life expectancy of the subject is at least one year.

 -  The subject has a lesion located in the internal carotid artery (ICA); the carotid
 bifurcation may be involved.

 -  The subject must have a minimum distance of 5 cm between the clavicle and bifurcation,
 as assessed by duplex Doppler ultrasound, computed axial tomographic (CT) angiography
 or magnetic resonance (MR) angiography.

 Exclusion Criteria:

 -  The subject was participating in another investigational trial that would interfere
 with the conduct or result of this study.

 -  The subject had dementia or a neurological illness that may confound the neurological
 evaluation.

 -  Presence of any one of the following anatomic risk factors:

 -  Previous radiation treatment to the neck or radical neck dissection

 -  Tracheostomy or tracheal stoma

 -  Laryngectomy

 -  Contralateral laryngeal nerve palsy

 -  Severe tandem lesions

 -  Inability to extend the head due to cervical arthritis or other cervical
 disorders

 -  A total occlusion of the target vessel.

 -  There was an existing, previously placed stent in the target artery.

 -  The subject had a known life-threatening allergy to the contrast media that cannot be
 treated.

 -  Subject had history of intolerance or allergic reaction to any of the study
 medications including aspirin, Clopidogrel bisulfate (Plavix®) or Ticlopidine
 (Ticlid®), heparin or Bivalrudin (Angiomax™). Subject was unable to tolerate a
 combination of aspirin and Clopidogrel/Ticlopidine.

 -  The subject had a GI bleed that would interfere with antiplatelet therapy.

 -  The subject had known cardiac source of potential emboli.

 -  Subject had a Hemoglobin (Hgb) level less than 8 gm/dL (unless on dialysis), platelet
 count < 50,000/mm3, or known heparin associated thrombocytopenia.

 -  Subject had documented atrial fibrillation in the 90 days prior to the procedure.

 -  The subject had a history of bleeding diathesis or coagulopathy including
 thrombocytopenia or an inability to receive heparin in amounts sufficient to maintain
 an Activated Clot Time (ACT) at > 250, or will refuse blood transfusion.

 -  The subject had atherosclerotic disease involving in the ipsilateral common carotid
 artery that precluded safe placement of the arterial sheath.

 -  The subject has other abnormal angiographic findings that indicate the subject is at
 risk for a stroke due to a problem other than that of the target lesion, such as:
 ipsilateral arterial stenosis greater in severity than the target lesion, cerebral
 aneurysm, or arteriovenous malformation of the cerebral vasculature.

 -  There is evidence of a carotid artery dissection prior to the initiation of the
 procedure.

 -  There is an angiographically visible thrombus.

 -  There is any condition that precludes proper angiographic assessment or makes
 percutaneous arterial access unsafe, e.g. morbid obesity, sustained systolic blood
 pressure > 180 mm Hg, tortuosity, occlusive disease, vessel anatomy, aortic arch
 anatomy, or cerebral protective system.

 -  Occlusion (TIMI 0 flow), or string sign of the ipsilateral common or internal carotid
 artery.

 -  There is evidence of bilateral carotid stenosis that would require intervention within
 30 days of procedure.

 -  There is evidence of a stroke within the previous 30 days of the procedure.

 -  There is a planned treatment of a non-target lesion within 30 days post procedure.

 -  There is a history of intracranial hemorrhage within the previous 3 months, including
 hemorrhagic transformation of an ischemic stroke.

 -  There is a history of an ipsilateral stroke with fluctuating neurologic symptoms
 within one year of the procedure.

 -  Female subjects who are pregnant or may become pregnant.