5.
Executive Summary - Clinical Studies and Information
Presented
herein is clinical information to support use of the PMA devices. The primary study to support safety and
effectiveness is the pivotal SAPPHIRE Study.
Additional clinical studies and information that may be relevant are
also provided.
SAPPHIRE Pivotal Clinical
Study
The Cordis SAPPHIRE clinical study was conducted as
the pivotal study to support the PMA application. Results demonstrate safety and effectiveness of the study devices
in treatment of carotid artery disease in patients who are at high risk for
surgery.
Background: SAPPHIRE was designed as a
multi-center, prospective, randomized trial comparing carotid stenting with
distal protection to carotid endarterectomy (CEA) in high-risk patients. The study design also included separate
stent and CEA non-randomized (or registry) arms. Patients who met all entry criteria, but were determined by the surgeon
to be too high-risk for CEA, and therefore unable to be randomized, were entered
into a separate, non-randomized stent arm.
Patients who met all entry criteria, but were determined by the
interventionalist to be too high-risk for stenting, and therefore unable to be
randomized, were entered into a separate, non-randomized CEA arm.
Enrollment in the randomized arm of SAPPHIRE was
discontinued on June 11, 2002 due to slow enrollment, the unwillingness of
surgeons to refer patients, competing non-randomized trials, and waning
physician interest in randomizing patients.
This did not compromise statistical analysis or interpretation of the
trial. The only consequence of early
stopping of the trial based on the noted administrative reasons is lower than
expected statistical power. Since
non-inferiority was still achieved statistically, this consequence was
successfully circumvented and the conclusions of the study are not
affected. Similarly, the decision to
not perform an interim analysis was based on administrative reasons and not on
statistical analysis; thus, there is no alpha-penalty to be paid for the final
analysis, nor does lack of the interim analysis negate the conclusions made
from the final results.
Primary Endpoint:
Composite
of major adverse events (MAE) including death, any stroke, and/or myocardial
infarction at 30-days post-procedure and MAE at 30-days post-procedure plus
death and/or ipsilateral stroke between 31 days and 12-months post-procedure.
Number
of Patients/Sites: The randomized arm of the
SAPPHIRE study enrolled 334 patients (167 stent patients and 167 CEA
patients). The non-randomized arms of
the SAPPHIRE study enrolled 406 stent patients and 7 CEA patients. Hence, a total of 747 patients were enrolled
into SAPPHIRE at 29 centers.
Study Devices:
SAPPHIRE
investigated the safety and effectiveness of carotid stenting with distal
protection utilizing the following Cordis devices:
§
Cordis
PRECISE™ Nitinol Stent System (5.5F & 6F)
§
S.M.A.R.T.™
.018” Nitinol Stent System (earlier version of the 6F PRECISE device)
§
ANGIOGUARD™
XP Emboli Capture Guidewire
§
ANGIOGUARD™
Emboli Capture Guidewire (earlier version of ANGIOGUARD XP)
Clinical use of the earlier version devices
(S.M.A.R.T. .018” and ANGIOGUARD) support the PMA devices in that the device
refinements and line extensions were implemented to enhance deliver-ability and
reduce profile, which is optimal for carotid artery procedures, and to provide
additional sizes to meet the needs of patient anatomies. The changes were minor and unrelated to
study endpoints. Delivery system
operating principles are the same, SMART Stents have the same finished design,
dimensions, and functional requirements as 6F PRECISE Stents, and the
ANGIOGUARD and ANGIOGUARD XP basket/filter wire components are identical. Hence, safety of the procedure,
effectiveness of the stent, and ability of the filter basket to capture emboli
and the force of the basket on the vessel wall are not impacted.
SAPPHIRE
utilized the noted over-the-wire (OTW) versions of PRECISE and ANGIOGUARD
devices. However, SAPPHIRE clinical
results also support rapid-exchange (RX) versions of these devices (Cordis
PRECISE™ RX Nitinol Stent System and ANGIOGUARD™ RX Emboli Capture
Guidewire). Device refinements
implemented to facilitate rapid-exchange use do not impact primary endpoints of
SAPPHIRE. Basic operating principles
are the same, the PRECISE stents used in the systems are the same, and the
basket/filter wire components of the ANGIOGUARD and ANGIOGUARD XP devices are
the same as the ANGIOGUARD RX device.
Hence, safety of the procedure, effectiveness of the stent, and ability
of the filter basket to capture emboli and the force of the basket on the
vessel wall are not impacted. The Food
& Drug Administration agreed that bench and animal tests, in conjunction
with the results of clinical testing of OTW devices, would be adequate to
support RX device safety and effectiveness.
Results:
Randomized Arm: For
stent patients, acute clinical results show that lesion success rate was 91.8%,
procedure success was 88.1%, device (stent) success was 91.2%, and ANGIOGUARD
success was 95.6%. The incidence of MAE
at 30 days was 4.8% for stent patients compared to 9.6% for CEA patients. The incidence of MAE at 360 days was 12.0%
for stent patients compared to 19.2% for CEA patients.
In comparing treatment arms
for MAE at 360 days, the stent arm was non-inferior to the CEA arm within the
designated 3% delta (-7.2% [-14.9%, 0.6%]).
The difference represented a trend for superiority of the stent arm (p =
0.067)
Stent Registry Arm: Acute clinical results showed that the lesion success rate was
90.4%. The procedure success rate was
87.9%. The device (stent) success rate
was 89.6%. The ANGIOGUARD success rate
was 91.6%. The incidence of MAE at 30
days was 6.9% and at 360 days was 15.8%.
In a test of the primary endpoint against the OPC,
despite the fact that the rate was numerically less than the OPC plus the
delta, the p value was found to be 0.2899.
In a test of the MAE rate when post 30-day non-neurological deaths are
not included, the p value was found to be <0.0001. The causes of these non-neurological deaths are well documented,
and consist of cardiac deaths, cancer deaths, renal failure, and respiratory
failure.
The
following clinical reports/information were generated from the SAPPHIRE
data.
§
SAPPHIRE
1 Year Results – Randomized Arm (Intent to Treat)
o
Appendix
I of the SAPPHIRE ITT Report provides a separate analysis of Randomized
Evaluable Patients
o
Separate
stratification of Randomized SAPPHIRE Patients by Anatomic and Co-morbid Risk
Factors is also provided with the SAPPHIRE 1 Year Randomized Arm Report.
§
SAPPHIRE
– 1 Year Results – Registry Arm
§
SAPPHIRE
– 1 Year Results – Stent Registry vs. CEA Randomized Results
§
Sub-analysis
of Non-randomized Stent patients vs. randomized CEA patients
§
Preliminary
SAPPHIRE 2-Year Results (Randomized ITT Arm)
§
Summary
of Reasons for Patient Entry in Non-Randomized Stent Arm
§
Justification
for Treatment of Asymptomatic High Surgical Risk Patients
§
Additional
Ultrasound Analysis
Conclusion: The results of the pivotal
study presented in the SAPPHIRE clinical summaries demonstrate safety and
effectiveness of the study devices in treatment of carotid artery disease in
patients who are at high risk for surgery.
Feasibility Clinical Study
Background: The Feasibility clinical
study began prior to SAPPHIRE under the same IDE. The intent of the study was to confirm device and procedure
safety prior to initiation of the SAPPHIRE pivotal study. The study was a multi-center, prospective,
open-label feasibility study evaluating the safety and effectiveness of de novo
or post-endarterectomy restenotic obstructive lesions in native carotid
arteries.
Primary
Endpoint: 30-day composite of major
adverse clinical events including death, any stroke, and/or myocardial
infarction.
Number of Patients/Sites: There
were 262 patients enrolled into the Feasibility Study at 33 investigational
sites. Of those patients, 177 were
treated with a stent alone (no distal protection) and 85 patients were treated
with stenting and distal protection.
Study Devices: Initially, only stent devices were utilized in this
study. An earlier version ANGIOGUARD
was introduced later. Ninety ANGIOGUARD
devices were used in 85 patients. Study
devices consisted of S.M.A.R.T. stent devices, 5.5F PRECISE stent device, and
ANGIOGUARD.
Initially,
a 7F, 120cm long, .035” guidewire lumen delivery system loaded with S.M.A.R.T.
Stents was utilized. The delivery
system was modified to taper from 6F proximally to 7F distal, utilize a 135cm
working length, and reduce the guidewire lumen to .018”. The delivery system was modified once more
to include a tapered tip (S.M.A.R.T.™ .018” Nitinol Stent System). Each of these delivery system versions was
loaded with the same S.M.A.R.T. Stents.
S.M.A.R.T.
devices differed only in the delivery system component. The delivery systems utilized the same
operating principle (sheath withdrawal to deploy stent) and consisted of
similar materials. The S.M.A.R.T. Stent
utilized in the Feasibility Study has the identical design, is comprised of the
same material, and has the same finished dimensions as the current 6F PRECISE
Stent that was used in the pivotal SAPPHIRE study.
The
5.5F PRECISE device was added to the study.
It provided a reduced profile delivery system for delivery of smaller
stent diameters (5-8mm). There are only
minor dimensional differences between S.M.A.R.T. and 5.5F PRECISE Stents. Basic design, material and performance
requirements are the same.
The earlier version ANGIOGUARD device, also utilized
in SAPPHIRE, has the same guidewire/basket component as the current ANGIOGUARD
XP device. Therefore, the ability to
capture emboli and the force of the basket on the vessel wall are the same as
ANGIOGUARD XP.
Results: The lesion success rate was 95.8%, procedure success was 90.4%,
device (stent) success was 92.3%, and ANGIOGUARD success was 86.7%. The cumulative Major Adverse Event (MAE)
rate through 30 days was 6.9% compared with the OPC of 12.7 (p=0.0018). The cumulative MAE rate through 1 year was
10.7%. The following clinical reports
were generated from the Feasibility Study data.
·
The
Cordis Nitinol Carotid Stent and Delivery System (SDS) in Patients with de novo
or Restenotic Native Carotid Artery Lesions Trial – Carotid Feasibility Trial –
Final Report
o
(includes
separate stratification by de novo or post-endarterectomy and by
investigational center)
·
Preliminary
Feasibility 2 and 3 Year Results
Conclusion: The results
presented in the Feasibility Study clinical summaries help support safety and
effectiveness of the devices and procedure in treatment of carotid artery
disease.
Background: The CASCADE Study was
sponsored by Cordis and conducted in Europe to help demonstrate safety and
performance of the S.M.A.R.T.™ Stent, and later, the ANGIOGUARD™ Emboli Capture
Guidewire in carotid artery procedures.
The study was a multi-center, prospective, open study.
Primary Endpoint: The
primary endpoint was ipsilateral stroke or procedural related death within 30
days of stent implantation. Patients
were excluded if they had evidence of medical or surgical risk factors.
Number of Patients: 121 patients with high-grade carotid artery stenosis were entered
into this study at 9 investigational sites between September 1998 and May
2001. Ninety (90) patients were treated
with the stent device alone. Thirty-one
(31) patients were treated with stenting and distal protection.
Study Devices:
S.M.A.R.T.
Stent* and ANGIOGUARD Emboli Capture Guidewire**
*The
S.M.A.R.T. Stent component is identical to the 6F PRECISE Stent component. During the course of the study, earlier
version delivery systems were used. The
delivery system was enhanced to provide a longer working length (135 vs. 120
cm), a smaller guidewire lumen (.018 vs. .035), a tapered 6/7F profile vs. a 7F
profile, and a tapered vs. a non-tapered tip (S.M.A.R.T. .018” Nitinol Stent
System).
**The
ANGIOGUARD device utilized in this study was an earlier version of the
ANGIOGUARD™ XP Emboli Capture Guidewire.
The primary component of the device (the basket component) was not
changed. Therefore, ability of the
device to capture emboli and the force of the basket on the vessel wall are the
same as the ANGIOGUARD XP.
Results: Of the 90 patients treated with stenting alone, there were no
deaths, 10% had a stroke (2 major) and 8% had a TIA at 30 days. Of the 31 patients treated with stenting and
distal protection, there were 0 deaths, no major strokes, 1 minor stroke for an
overall event rate of 3.2% at 30 days in these patients. The combined incidence of death, stroke or
TIA at 30 days was 14.9% in both patient groups. The following clinical report was generated from the CASCADE
study data:
·
The
Cordis SMART Self-Expandable Stent in Carotid Artery Disease (CASCADE) Study
Conclusion: The results
presented in the CASCADE clinical summary help support safety and effectiveness
of the carotid stenting procedure using Cordis devices.
Background: Multiple
centers conducted investigator-sponsored studies utilizing Cordis devices. The studies were not sponsored, funded, or
monitored by Cordis, nor were the events adjudicated. Each study utilized its own protocol. Hence, patient populations may not be consistent among the
various centers and, in most cases, are not consistent with the SAPPHIRE
patient population. However, Cordis has
made a good faith effort to obtain safety data from the sites in a concise and
consistent manner in order to provide an overall summary. To do this, Cordis requested information
from the sites to capture baseline demographic, procedural and Cordis device
data and subsequent adverse events through 30-days. The data were collected by Harvard Clinical Research Institute
(HCRI) and entered into a database for data analysis.
Primary Endpoint:
The
primary endpoint utilized to assess results of these studies was a composite of
major adverse events (MAE) defined as death, any stroke, and/or myocardial
infarction at 30 days.
Number of Patients/Sites: A total of 491 patients were enrolled at thirty-four
centers.
Study Devices:
The
Cordis devices utilized were PRECISE Stent devices, S.M.A.R.T. Stent devices,
the ANGIOGUARD™ Emboli Capture Guidewire, and the ANGIOGUARD™ XP Emboli Capture
Guidewire. In some cases, it is
possible that sponsors used Cordis stents with competitor distal protection
devices, or competitor stents with the Cordis distal protection devices.
Results: Procedure success at 30 days was 93.8%. Cumulative MAE through 30 days was 4.3%. Detailed results are provided in the
clinical summary entitled “The Cordis Nitinol Carotid Stent and Delivery System
(SDS) Summary of Individual Site Sponsored Carotid IDE Studies – 30 Day Report”
provided in this panel pack.
Conclusion: The results
of the site-sponsored studies help support safety and effectiveness of carotid
stenting with distal protection using Cordis devices.