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.
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% . Nearly half of its survivors are
functionally incapacitated .
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 . 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. . 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 . 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 , incomplete initial aneurysm occlusion,
rupture and large aneurysm size were all associated with significant recanalization. Johnston
 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%) .
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 . 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  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 .
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 . 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 . 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 .
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.  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 . 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 . About 80-90% of the aneurysms are
small and only 10-20% are large and giant .
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 . In a Study of the natural history of aneurysms to determine the risk of
rupture, Juvela  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.  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).  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 . 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  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 .
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
- Any neurological morbidity and mortality (evaluated at time of >150-day angiographic
- Bleeding rate of target aneurysms, including rebleeding of target ruptured aneurysms (at
- Recurrence rate/recanalization (evaluated at time of >150-day angiographic follow up)
- Retreatment rate (at one year)
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.
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.
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.
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.