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Study Title Principal Investigator
The Medtronic CoreValve Evolut R US Clinical Study
Transcatheter aortic valve implantation (TAVI) has become a routine treatment option at specialized heart centers treating patients with severe aortic stenosis who are at high risk for surgical aortic valve replacement (SAVR). Medtronic has developed modifications to the Medtronic CoreValve System Transcatheter Aortic Valve frame and delivery catheter system to enable recapture of the device before it is fully released from the delivery system. These modifications are incorporated in the CoreValve Evolut R System. The purpose of the study is to evaluate the safety and efficacy of the CoreValve Evolut R System in patients with severe symptomatic aortic stenosis who are considered at high through extreme risk for surgical aortic valve replacement. This is a prospective, single arm, historical controlled, multi-center study. This study will involve no more than 250 subjects in up to 25 sites. The study population includes males and females with severe symptomatic aortic stenosis who are considered at high through extreme risk for surgical aortic valve replacement. Subjects will be followed up to 5 years following implantation. Study endpoints are safety endpoints and efficacy endpoints. Safety endpoints are: All-cause mortality rate, stroke (disabling) rate, incidence of permanent pacemaker implant rate at 30 days. Efficacy endpoints are: Device success rate, Resheath and recapture success rate, percent of subjects with mild prosthetic regurgitation at early post-implant, hemodynamic performance metrics at 30 days. Statistics/analysis: Subjects who are taken to the procedure room for implantation will comprise the study population evaluated for the study objectives and associated endpoints. An initial analysis will be performed when both of the following conditions are met: 1. The first 150 consecutive implanted subjects have completed their 30 day follow-up. 2. A total of 25 resheath or recapture attempts inclusive of all valve sizes, have been performed. The final analysis will be performed after a minimum of 150 subjects but no greater than 250 subjects are implanted with the study device and followed for 5 years. All endpoints are descriptive and no statistical hypothesis test will be performed.
Recruiting | Aortic Stenosis | Multisite
Vaughn Starnes
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COAST: Coiling of Aneurysms Smaller Than 5mm With Hypersoft® and Hydrogel Coils
1.0 INTRODUCTION 1.1 Background Intracranial aneurysms (IAs) are common cerebrovascular abnormalities. The prevalence of IAs has been reported to be 0.8-2.0% of the population. [1-3] The most common presentation of IAs is subarachnoid hemorrhage (SAH), the annual incidence of which varies by geographic region from 10 to 20 per 100,000. [4 5] SAH is a devastating injury with a case-fatality rate of 51% [5]. Nearly half of its survivors are functionally incapacitated [6]. There is limited data on the natural history of small intracranial aneurysms. According to the International Study of Unruptured Intracranial Aneurysms, the risk of spontaneous aneurysm rupture is related to aneurysm size and location. ISUIA found aneurysms < 10 mm in diameter, as opposed to aneurysms 10-24 mm and >25 mm, had relative risks of rupture of 11.6 and 59, respectively. Further follow-up from this cohort showed 5-year bleeding risks of 0%, 2.6%, 14.5%, and 40% for aneurysms less than 7 mm, 7--12 mm, 13--24 mm, and 25 mm or greater, respectively. Many other authors (Juvela 2000 and Weir 2002) also suggest the risk of small aneurysm rupture is relatively low. The Sapporo SAH Study group suggests that while the overall rupture risk of small aneurysms is low, the aneurysm size ratio is a strong predictor of aneurysm rupture in small (<5mm) intracranial aneurysms [7]. However, some authors and unpublished data (MUSC) demonstrate that approximately one-third of all ruptured aneurysms are less than 4 mm in size. Endovascular coiling of intracranial aneurysms has been shown to be safe and efficacious in the treatment of intracranial aneurysms. The International Subarachnoid Aneurysm Trial (ISAT) has shown that endovascular coiling can reduce morbidity and mortality compared to clipping of aneurysms in the setting of SAH. [8]. The goal of endovascular coiling is to prevent rupture or rebleeding by isolating an aneurysm from the normal blood circulation without narrowing the parent vessel. A main concern of endovascular treatment is the long-term durability of treatment, that is to say that it is possible for the aneurysm to recanalize (recur) after it has been treated with coils [9]. Some factors in recanalization are incomplete initial occlusion, large aneurysm size, ruptured aneurysm, partially thrombosed aneurysm, and compaction of the coil mass within the aneurysm [9 10]. In a Study by Nguyen [11], incomplete initial aneurysm occlusion, rupture and large aneurysm size were all associated with significant recanalization. Johnston [12] concluded the degree of occlusion after initial treatment to be a strong predictor of the risk of subsequent rupture, which justified attempts to completely occlude aneurysms. Two series of small unruptured intracranial aneurysms [13 14] found recurrence rates between 5.9% and 16.9% with retreatment rates of 1.7% and 2.9%. The majority of retreatments were in small wide necked aneurysms. However, the recurrence rates of small aneurysms is much less than those of large aneurysms (71% vs 35%) [15]. The other main concern with the treatment of small aneurysms (less than 4 mm) is safety, namely the concern of intraprocedural rupture or thromboembolic events. The ATENA Study showed that the risk of intraprocedural aneurysm rupture was significantly higher in small aneurysms (3.7% for 1-6 mm vs 7% for 7-15 mm; p= 0.008). The rate of failure of EVT was significantly higher in very small unruptured aneurysms compared to larger aneurysms (13.7% vs 3.3% respectively). This is likely related to several factors. Microcatheterization of the aneurysm sac may be challenging due to aneurysm size and placing even the smallest coils, maybe challenging in small aneurysms. In the same series as above [13 14], a 10.4% overall procedural complication rate was found. There were 24 embolic events, 11 coil protrusions and 4 aneurysm ruptures, while Oishi found a 3.8% thromboembolic event rate and a 1.4% risk of aneurysm rupture. Nguyen et al reported an intraprocedural rupture rate of 11.7% in aneurysms less than 3 mm in diameter [16]. In a meta-analysis, Brinjikji et al found a procedural rupture rate of 8.3% in small aneurysms while Spiotta et al demonstrated a 13.5% rate of intraprocedural rupture in ruptured aneurysms less than 4 mm [17] Other studies have found morbidity and mortality rates that range from 0.8%-7% and 0-1.4% [13 14 18]. The introduction of the Microvention HyperSoft® 3D line of coils with sizes from 1 to 5mm may help reduce these historical risks of failure to treat and intraprocedural rupture. The complex shape of the coils may allow for stable framing of the aneurysms followed by dense packing of the aneurysm sac and neck, therefore preventing recurrence. The softness of the coils may allow for increased confidence and safety when treating these aneurysms, which may be expressed as a reduction of intraprocedural complications. 1.2 Pathophysiology and Prevalence of Aneurysms A cerebral or intracranial aneurysm is a focal dilation of an artery in the brain that results from a weakening of the inner muscular layer (the intima) of a blood vessel wall. The pathogenesis of intracranial aneurysms remains incompletely understood. Most aneurysms arise sporadically but occasionally they may be: dissecting (resulting from a luminal endothelial tear), traumatic (usually within 2-3 weeks after severe head injury) or mycotic (as a result of embolism of infected material). Aneurysm etiology is multifactorial, including congenital medial arterial wall defects, degenerative changes, and accruing hemodynamic stress, particularly at sites of turbulent blood flow. Contributing factors include connective tissue disorders, hypertension, anatomy variations, atherosclerosis, trauma, mycosis, and tumors. Epidemiological studies have already identified aneurysm-specific risk factors such as size and location, as well as patient-specific risk factors, such as age (higher in adults), sex (higher in females), and presence of medical comorbidities, such as hypertension. In addition, exposure to certain environmental factors such as smoking has been shown to be important in the formation of IA. Furthermore, substantial evidence proves that certain loci contribute genetically to IA pathogenesis. Genome-wide linkage studies using relative pairs or rare families that are affected with the Mendelian forms of IA have already shown genetic heterogeneity of IA, suggesting that multiple genes, alone or in combination, are important in the disease pathophysiology [19]. Aneurysm wall thickness varies throughout the sac. The thickness is greatest at the neck and least at the fundus. Compared to small aneurysms, calcification and atheromas are more commonly seen in large aneurysms. Macrophages, present in all stages of atherosclerosis, secrete lytic enzymes (e.g., elastases, collagenases, metalloproteases), lead to the destruction of connective tissue and erosion of the arterial wall. Smooth muscle cell apoptosis and elastin/collagen fiber reconstruction mechanisms contribute to vessel wall weakening [20]. The weakening of aneurysm walls has been demonstrated in histological studies that found degeneration of endothelial cells and internal elastic lamina and thinning of the medial layer [21]. Aneurysm wall tensions and stressors have been noted to be an important contributor to growth, remodeling and rupture in aneurysms. Focal turbulence and discontinuity of the normal architecture at vessel bifurcations may account for the propensity of saccular aneurysm formation [22]. The frequency of cerebral aneurysms is difficult to ascertain because of variation in the definitions of the size of aneurysm and modes of detection. Autopsy series cite prevalences of 0.2-7.9%. Prevalence ranges from 5-10%, with unruptured aneurysms accounting for 50% of all aneurysms. Pediatric aneurysms account for only 2% of all cerebral aneurysms. In the United States, the incidence of ruptured aneurysms is approximately 12 per 100,000 individuals or 30,000 annual cases of aneurysmal SAH. The frequency of cerebral aneurysms has not declined in recent years. [22] Saccular (berry) aneurysms constitute 90% of all cerebral aneurysms and are usually located at the major branch points of large arteries. Saccular aneurysms frequently rupture into the subarachnoid space, accounting for 70-80% of spontaneous subarachnoid hemorrhage. Annually, 15,000 American patients have SAH from aneurysms with a maximum diameter <7 mm and consequently experience irreparable morbidity and severe mortality. The majority of their aneurysms were unruptured, single, asymptomatic, and even smaller at some point before rupture [23]. Fusiform or arteriosclerotic aneurysms are elongated outpouchings of proximal arteries that account for 7% of all cerebral aneurysms and infectious or mycotic aneurysms usually situated peripherally comprise 0.5% of all cerebral aneurysms. Small aneurysms are less than 10 mm in diameter. Larger aneurysms are 10-25 mm and giant aneurysms are greater than 25 mm in diameter [24]. About 80-90% of the aneurysms are small and only 10-20% are large and giant [5]. Both ruptured and unruptured aneurysms are candidates for endovascular therapy. The natural history of unruptured intracranial aneurysms is still unclear and is influenced by many factors such as previous subarachnoid hemorrhage from another aneurysm, history of cigarette smoking, coexisting medical conditions, and aneurysm characteristics such as size, location, and morphology [25]. In a Study of the natural history of aneurysms to determine the risk of rupture, Juvela [26] followed 142 patients with 181 unruptured aneurysms for a mean of 13.9 years (range 0.8 - 30 years) to death or subarachnoid hemorrhage. The annual rupture rate was 1.4%. The median diameter of the aneurysm followed was 4 mm at diagnosis. Fourteen of the intracranial hemorrhages (ICH) were fatal; the authors concluded that unruptured aneurysms should be treated if technically feasible irrespective of size. 1.3 Treatment options for intracranial aneurysms The wide availability and use of noninvasive imaging has increased the frequency of incidental discovery of intracranial aneurysms. There are two broad categories of intracranial aneurysms: those that have ruptured, creating subarachnoid hemorrhage and those that are unruptured. Subarachnoid hemorrhage from aneurysm rupture is a devastating event. It is estimated that about 40% of individuals whose aneurysm has ruptured do not survive the first 24 hours: up to another 25% die from complications within 6 months. Early diagnosis and treatment are important. [27] Aneurysm treatments include medical, surgical and endovascular therapies. Medical therapy involves general supportive measures and prevention of complications for individuals who are in the periprocedural period or are poor surgical candidates and includes: control of hypertension, calcium channel blockers, prevention of seizures and antibiotic therapy for those presenting with infectious aneurysms. In the microsurgical approach, a section of the skull is removed. The brain tissue is then spread apart to reveal the aneurysm and a small metal clip is placed at the base of the aneurysm to block the flow of blood. Alternative microsurgical techniques involve proximal or Hunterian ligation, wrapping of the aneurysm or trapping (i.e., a combination of proximal and distal vessel occlusion). [22] Endovascular therapy (EVT) involves insertion of a catheter into the femoral artery in the patient's leg and navigating it though the vascular system into the head and aneurysm. Once there, several treatment options are available: detachable coils may be deployed within the aneurysm to occlude it from the parent artery blood flow, this may be done alone or by using an adjunctive technique such as balloon remodeling or intracranial stenting of the parent artery. In balloon remodeling, a temporary occlusion balloon is inflated across the neck of the aneurysm while the coils are introduced. The balloon functions to prevent the prolapse of coils into the parent vessel. Although the temporary occlusion balloons provide support for the coils during their introduction, sometimes the coil can prolapse into the parent artery immediately after balloon deflation [28]. Also very wide-necked or irregular shaped aneurysms may lack a neck structure making coil placement difficult or impossible. These aneurysms may have an intracranial stent placed in the parent artery crossing the neck of the aneurysm. The coils are then introduced through the stent in order to help jail them within the aneurysm. Parent vessel occlusion, although not as common as aneurysm coiling is performed mostly on fusiform and acute dissecting arteries and involves the complete occlusion of the parent vessel with coils and sometimes embolic liquid. Embolization with detachable coils is a safe and effective treatment of brain aneurysms. The 1-year results of the ISAT Study [29] of endovascular coiling of aneurysms (considered suitable for both neurosurgical clipping and endovascular coiling) yielded a significant advantage over neurosurgical clipping in terms of death and severe disability. Of patients allocated to endovascular treatment, 250 of 1063 (23.5%) were dead or dependent at 1 year compared with 326 of 1055 (30.9%) patients allocated to neurosurgical clipping. As such, the absolute risk reduction was calculated as 7.4% (95% CI: 3.6-11.2; P = .0001) in favor of endovascular treatment. Because of this significant difference between coiling and clipping, treatment of patients with a ruptured intracranial aneurysm changed significantly over the past years, particularly in Europe. In many centers, coiling has become the method of choice when both coiling and clipping are considered suitable in the individual patient. At 5 years, 11% (112 of 1046) of the patients in the endovascular group and 14% (144 of 1041) of the patients in the neurosurgical group had died. The risk of death at 5 years was significantly lower in the coiling group than in the clipping group [8]. Although endovascular coiling has been shown to be a safe and effective treatment, some of these same patients require repeat treatment for recurrence of an aneurysm [30 31]. Published series regarding mid and long-term clinical outcome and follow up angiographic findings confirm that recanalization may occur in up to 33% of treated patients, which also tends to increase in the aneurysms with wider necks and larger sizes [2 30 32 33]. In the case of coiled aneurysms, large aneurysms are more likely to recur than smaller ones and ruptured aneurysms are more likely to recur than unruptured ones [11 30]. Over the last decade, there have been significant improvements of the endovascular techniques and the development of a wide range of devices including 3-D coils, spherical coils, and complex coils. The introduction of balloon and stent remodeling techniques resulted in further expansion of the devices and techniques available to neurointerventionalists, and made EVT possible for greater percentage of patients. Enhancement of platinum coil thrombogenicity has been attempted by surface modifications using Dacron® fibers, bioabsorbable polymers (Cerecyte® coil, Codman/Micrus Endovascular; Matrix®coil, Boston Scientific) or hydrogel coatings (HydroCoil®, MicroVention). The use of non adhesive embolic agents such as Onyx® (ev3) for aneurysm embolization has proven to be an occlusive method that, in some patients, completely fills and conforms to the unique geometry of the aneurysm cavity, resulting in complete aneurysm obliteration. A relatively new technique being used is Parent Vessel Reconstruction using stents (Neuroform® microstent Boston Scientific, Enterprise™ Codman®, Pipeline Embolization Device, Covidien) not just to coil the aneurysm but to change the parent vessel configuration, redirect the flow of blood to help reduce the wall shear stress on the aneurysm and to promote tissue growth over the neck of the aneurysm. 2.0 STUDY OBJECTIVES The primary objective of this post-marketing Study is to assess the clinical and imaging outcomes in the endovascular treatment of small (≤ 4.9 mm) intracranial aneurysms utilizing the HyperSoft® 3D and HyperSoft® Helical coils (or HydroFrame®, HydroFill® and HydroSoft® (3D and Helical) coils in Phase 2) specifically designed for the treatment of small aneurysms. The neck of the aneurysm may be protected during coiling with a balloon or stent indicated for use in the neurovasculature. It is hypothesized that framing, filling and neck finishing using HyperSoft® 3D, HydroFrame®, HydroSoft® 3D and HyperSoft® Helical coils, aided by balloon remodeling or stent assistance where appropriate, will yield better occlusion rates, may lower recanalization and retreatment rates and be safer (reduce intraprocedural aneurysm rupture rates) compared to historical data using earlier generation technology. 2.1 Primary Endpoints - Efficacy: Raymond-Roy grading scale (RRGS) of 2 or better occlusion on follow up angiography performed >150 days post embolization, not requiring retreatment - Safety: Freedom from imaging-confirmed new post-procedural hemorrhage and ischemic stroke associated with a 4-point worsening in NIHSS within 48 hours of aneurysm treatment or any new aneurysmal SAH secondary to treated aneurysm 2.2 Secondary Endpoints - Any neurological morbidity and mortality (evaluated at time of >150-day angiographic follow up) - Bleeding rate of target aneurysms, including rebleeding of target ruptured aneurysms (at one year) - Recurrence rate/recanalization (evaluated at time of >150-day angiographic follow up) - Retreatment rate (at one year)
Recruiting | | Not Multisite
Jonathan Lena
Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial
Prevention of stroke involves managing and treating risk factors. Most strokes are caused when blood flow to a portion of the brain is blocked. One place this often happens is in the carotid artery. This blockage is called atherosclerosis or hardening of the arteries. The purpose of this trial is to determine the best way to prevent strokes in people who have a high amount of blockage of their carotid artery but no stroke symptoms related to that blockage. Each eligible participant will be evaluated to determine which procedure(s) is best for him/her. All participants will receive intensive medical treatment. In addition, participants will be randomized to receive the selected procedure or not. The trial will be conducted in the United States and Canada by physicians carefully selected on their ability to perform the procedures at low risk. Another key component of the trial is that important stroke risk factors, including hypertension, diabetes, high cholesterol, cigarette smoking, physical activity, and diet will be managed intensively. Participants will remain in the study for 4 years.
Recruiting | | Multisite
Thomas Brott
AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke
ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause. Eleven hundred subjects will be recruited over 2.5 years at 120 sites in the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 4 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage.
Recruiting | | Multisite
Mitchell Elkind
Global Observational Study to Evaluate the Correlation Between Coronary and Carotid Atherosclerotic Disease (CAD) and Links with Clinical Outcomes
Observational study to collect F/U imaging & clinical endpoint data from pts. who successfully completed baseline coronary IVUS (intravascular ultrasound) imaging in the dal-PLAQUE 2 (DP2) study to determine the correlation & clinical relevance of such imaging as related to coronary artery disease (CAD). Pts. who have had baseline angiography/IVUS, with or w/o baseline carotid ultrasound but NOT undergone follow-up angiography/IVUS as part of DP2 will have F/U angiogram/IVUS within 18-27 mos. of baseline imaging. Pts. who have had baseline carotid ultrasound but NOT undergone a F/U carotid ultrasound as part of DP2 will have follow-up carotid ultrasound within 18-27 mos. of baseline imaging. Main objectives is to compare: extent of atherosclerosis in coronary arteries with the extent of atherosclerosis in carotid arteries at a single point in time. Pts. who have successfully undergone baseline IVUS imaging, with or w/o baseline carotid ultrasound, in DP2 will be included. Pts., who successfully completed baseline angiography/IVUS in DP2, with or w/o baseline carotid ultrasound, will be scheduled for final F/U angiography/IVUS any time between 18-27 mos. after DP2 baseline imaging. Pts. who successfully completed baseline carotid ultrasound in DP2 will be scheduled for F/U carotid ultrasound any time between 18 -27 mos. after DP2 baseline imaging. Endpoints: death, death from coronary heart disease, resuscitated cardiac arrest, non-fatal MI, stroke, hospitalization for documented acute coronary syndrome, coronary revascularization procedure & carotid artery surgery or angioplasty. Pts. will have annual phone contact for 3 yrs. to check for the occurrence of cardiovascular & cerebrovascular clinical endpoints. Imaging parameters from this study will be combined with the imaging data from DP2 to compare coronary & carotid atherosclerosis extent at baseline & rate of progression up to 2 yrs.
Recruiting | | Not Multisite
Leonardo Clavijo
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Medtronic CoreValve® U.S. Expanded Use Study
The primary objective of the study is to evaluate the safety and effectiveness of the Medtronic CoreValve® System (MCS) in a subset of subjects excluded from the U.S. Extreme Risk Pivotal Trial population due to one or more additional co-morbidities, as measured by a composite of all-cause death or major stroke at 12 months, in the treatment of symptomatic severe aortic stenosis in subjects necessitating aortic valve replacement. Subjects enrolled in this study have a predicted operative mortality or serious, irreversible morbidity risk of ≥50% at 30 days associated with surgical aortic valve replacement.
Recruiting | Aortic Stenosis | Multisite
Vaughn Starnes
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New study helps predict the risk of falling in people post-stroke
Taking precautions to prevent falling after stroke is very important. Falls can cause broken bones, increased disability, and even death. The purpose of this study is to find out whether we can train stroke patients to walk in a way that lowers their risk of falling. The study will look at the advantages and disadvantages of restoring symmetry in the walking patterns of stroke survivors. The research team is looking for stroke patients who are interested in joining the study.
Recruiting | stroke | Not Multisite
James Finley, PhD
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