SUMMARY OF SAFETY AND EFFECTIVENESS DATA

1.  **GENERAL INFORMATION**

**Device Generic Name:** Implant Clip and Delivery System

**Device Trade Name:** PAS-Port^®^ Proximal Anastomosis System

**Applicant's Name and Address:** Cardica, Inc.

900 Saginaw Drive

Redwood City, CA 94063

**510(K) Number:** K030434

**Date of Panel Recommendation:** April 22, 2005

**Date of Notice of Clearance to the** Pending

**Applicant:**

2.  **INDICATIONS FOR USE**

The PAS-Port^®^ System is intended to create an everting anastomosis
between the aorta and an autologous vein graft.

3.  **CONTRAINDICATIONS**

The PAS-Port^®^ Proximal Anastomosis System is contraindicated in:

-   Patients with target vessels during conventional surgical
    anastomoses that would typically not be created due to the presence
    of palpable disease. Such determination may also be based upon
    echocardiographic demonstration of either mural (e.g. calcification)
    and/or intimal (e.g. plaque, exudates) disease.

-   Patients with target vessels less than or equal to 18 mm in outside
    diameter and with wall thicknesses that would not be acceptable for
    a hand-sewn anastomosis.

-   Patients with conduit vessels that would not typically be used for
    bypass grafting procedures.

-   Patients with conduit vessels that have an outside diameter of less
    than 4.0 mm or greater than 6.0 mm, or with double wall thicknesses
    greater than 1.4 mm.

4.  **WARNINGS AND PRECAUTIONS**

See additional *Warnings and Precautions* in the PAS-Port^®^ Proximal
Anastomosis System Instructions for Use.

5.  **DEVICE DESCRIPTION**

The Cardica**^®^** PAS-Port**^®^** Proximal Anastomosis System is used
to facilitate creation of proximal vein graft anastomoses to the aorta
in CABG procedures. The Cardica^®^ PAS-Port^®^ System delivers an
Implant designed to create an anastomosis between a large target vessel
(e.g. aorta) and small caliber conduit (e.g. saphenous vein). The
Implant is a self-closing stainless steel clip that creates a complete
end-to-side anastomosis, which is functionally equivalent to a standard
hand-sutured anastomosis. The PAS-Port^®^ System is contained in a
package that is designed to facilitate attachment of the conduit to the
Implant, as well as to ensure that the conduit (after attachment to the
System and before deployment) is kept moist and vital. The content of
the tray consists of the Delivery Device, Cartridge with an Implant
attached to its end, a Pull-Through Tool, and Poke-Through Tools.

##################### **The Implant**  {#the-implant .unnumbered}

The Implant is made of 316 L medical grade Stainless Steel. The Implant
contains nine barbed, inner flange tines, over which the vein graft is
everted, and which are designed to penetrate and capture the vein graft
(Figure 1). The Implant is initially configured in a compressed state.
During deployment it expands and forms an inner and outer flange that
secures it in place.

![](media/image1.png){width="2.1354330708661418in"
height="1.7598425196850394in"}

**Delivery Device**

The Delivery Device integrates the hole making mechanism and the Implant
deployment system into a single device with a single user interface,
where one continuous rotation of a knob completes the creation of a
proximal anastomosis.

The Delivery Device contains a Cutter system, which is comprised of a
spring-loaded cylindrical spinning Cutter, an Auger used to capture the
cut section of the aortic wall, and an Introducer that secures the
aortotomy during insertion of the Implant (Figure 2).

![](media/image2.png){width="3.2574803149606297in"
height="2.377952755905512in"}![](media/image2.png){width="1.8791338582677166in"
height="1.741732283464567in"}![](media/image3.wmf){width="1.3751968503937009in"
height="1.1807086614173228in"}

**Principles of Operation**

#####################  {#section .unnumbered}

##################### **Vein Graft Loading**  {#vein-graft-loading .unnumbered}

The graft conduit is harvested using standard techniques. Clips should
not be used to occlude side branches. A gauge is provided to determine
the inflated outer diameter of the conduit and the double wall
thickness, which should be between 4 and 6 mm and no greater than 1.4
mm, respectively.

Conduit loading is accomplished in a 3 step process: The first step is
to insert the conduit through the Cartridge and Implant with the help of
a Pull-Through Tool (Figure 3-A); the end of the conduit attached to the
Pull-Through Tool is cut off and discarded. The conduit is then everted
over the Implant's inner flange tines (Figure 3-B). In the last step a
Poke-Through Tool is used to attach the conduit to the Implant (Figure
3-C). The recess surrounding the Cartridge and Implant is designed to be
filled with a physiologic crystalloid solution, which ensures that the
conduit is kept hydrated until the time of deployment (Figure 3-D). This
loading process minimizes endothelial damage.

![](media/image5.png){width="6.0in" height="4.489763779527559in"}

# Creation of the Anastomosis 

1.  Immediately before deployment, the Cartridge is inserted into the
    Delivery Device. The Delivery Device is prepared for deployment by
    moving the Safety Switch to the unlocked position. The Delivery
    Device is then positioned on the target vessel, ensuring firm
    contact between the Device and the adventitial surface of the target
    vessel. Deployment is accomplished through a continuous clock-wise
    rotation of the Knob on the Delivery Device. The rotation initiates
    and completes the aortotomy; a small section of the aortic wall is
    removed and secured within the device. Continued rotation completes
    the Implant deployment and separation from the Delivery Device
    (Figures 4 & 5). A soft bulldog clamp is then placed at the end of
    the conduit to prevent blood loss through the graft lumen according
    to general surgical practice.

![](media/image6.png){width="5.5in" height="4.218897637795275in"}

![](media/image7.wmf){width="1.8909448818897638in"
height="1.6043307086614174in"}![](media/image8.wmf){width="1.8909448818897638in"
height="1.6043307086614174in"}![](media/image9.wmf){width="1.8909448818897638in"
height="1.6043307086614174in"}![](media/image10.wmf){width="1.8909448818897638in"
height="1.6043307086614174in"}

2.  The Implant's inner and outer flanges compress the aortic wall.
    Stainless Steel becomes stiffer as its shape is changed and
    therefore the Implant is at its strongest configuration after
    deployment. This artistic rendering shows a profile view of the
    Implant with the graft attached to the aortic wall (Figure 6a). The
    everted section of the graft facilitates sealing by acting like a
    gasket. The implant has been successfully tested for fatigue life in
    a test environment simulating 10 years of implantation. The
    Implant's inner flange tines that have pierced the everted vein
    graft are flush with the intimal surface of the aorta. There is no
    metal in the orifice of the graft and the design of the implant
    promotes a wide and patent lumen (Figure 6b).

![](media/image11.png){width="2.4895833333333335in"
height="2.464583333333333in"}

![](media/image12.png){width="2.2465277777777777in"
height="2.495833333333333in"}

The design of the PAS-Port**^®^** System requires placement of the
proximal anastomosis before the distal anastomosis can be completed. As
per standard surgical practice, graft routing can be accomplished
through careful selection of the anastomotic site on the target vessel,
careful determination of appropriate graft length while the heart is
engorged, and the placement of individual stay stitches along the course
of the graft as deemed necessary. For conduits that target the left
lateral wall of the heart, left posterior or left anterior sections of
the myocardium, anastomoses should be placed on the lesser curvature or
left lateral wall of the ascending target vessel or aortic arch. For
conduits that target the right lateral or right posterior surface of the
heart, anastomoses should be placed on the anterior surface of the
ascending target vessel and can be routed to the left of or over the
right atrial appendage.

The integrated design of this product allows rapid deployment in a
non-clamped target vessel, such as the aorta, and may prove to be a
valuable asset in beating heart surgery procedures. Key features of the
PAS-Port**^®^** design are:

1.  Minimal trauma to endothelial surfaces during graft loading and
    implant deployment

2.  Minimal amount of foreign surfaces exposed to blood post deployment

3.  Large effective orifice of the anastomosis

4.  Low implant profile height that reduces the likelihood of graft
    kinking

5.  Secure attachment of implant to aortic wall

6.  Rapid and consistent creation of a proximal anastomosis

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6.  **ALTERNATIVE PRACTICES AND PROCEDURES**

    1.  *Description of Hand-sewn Technique for Creation of a Proximal
        Anastomosis*

The gold standard for surgical bypass therapy is to use both venous and
arterial grafts to bridge coronary lesions. For venous bypass grafting,
a proximal anastomosis to the aorta and a distal anastomosis to a
coronary target vessel must be performed by the surgeon.

Current techniques for performing a proximal anastomosis of a vein graft
to the thoracic aorta have several limitations. The aorta must be
clamped with partially or totally occluding vascular clamps to interrupt
blood flow to the area of the aortic wall to which the vein will be
anastomosed. Clamping of atheromatous plaques in the aortic wall may
result in liberation of plaques and tissue fragments with a possible
consequence of cerebral or distal organ emboli, which can result in
organ dysfunction such as strokes, renal failure, or intestinal
ischemia. In addition advanced aortic disease may limit areas suitable
for clamping.

A conventional hand--sutured anastomosis is created via a process
requiring a surgeon and an assistant. Eight to fourteen evenly--spaced
sutures must be precisely placed around the periphery of a limp,
thin--walled graft vessel to connect it to the patient's clamped aorta.
This process is time consuming and, therefore, increases time under
anesthesia as well as time in the operating suite. Both of these factors
have implications with respect to patient outcomes and procedural costs.
Furthermore, hand-sutured anastomoses are dependent upon the particular
anatomy of the patient and the skills of the surgeon.

2.  *Other anastomosis devices cleared by the FDA*

To date there are a total of three devices cleared by the FDA for
marketing within the US to facilitate creation of a proximal anastomosis
in cardiac surgery. The predicate device for the PAS-Port^®^ Proximal
Anastomosis System is the Symmetry Connector from St. Jude Medical. This
device consists of a Nitinol implant and its respective deployment
system. In preparing for deployment, the surgeon attaches the graft to
the implant. Then the aortotomy is created with a separate aortic
cutter. The aortotomy is covered with a finger to prevent hemorrhage. In
a final step the surgeon inserts the deployment tool into the aortotomy
and releases the Nitinol implant. The system was cleared May 21, 2001
(K003446) based on European clinical trial data and has been used in the
creation of more than 40,000 proximal anastomoses. In December, 2004,
St. Jude Medical announced that the company would no longer distribute
this product in the US.

The second product cleared in the US was the CorLink device developed by
Bypass Inc. and distributed through Cardiovations, a J&J subsidiary.
This product was cleared by the FDA December 26, 2001
([K011589](http://www.fda.gov/cdrh/pdf/k011589.pdf)) based on European
clinical trial data. Similar to the Symmetry device this product
consists of a Nitinol implant and its respective deployment system. The
deployment system consists of a base tool into which an aortic cutter is
placed to create the aortotomy. The aortic cutter is replaced by the
delivery device for deployment of the implant. The base tool secures the
aortotomy during tool transition and prevents hemorrhage.

The third product cleared by the FDA is the Spyder System, a product
currently distributed by Medtronic. The system has been cleared in July
3, 2003 (K031623). The Spyder is a proximal anastomosis system that uses
individual Nitinol clips to attach a graft to the aorta. The system
consists of a separate aortic cutter and deployment tool. In order to
create a proximal anastomosis, the surgeon attaches the graft to the
deployment tool by everting the graft over the implants. Similar to the
Symmetry Connector, the surgeon creates the aortotomy by manually
spinning the aortic cutter. The cutter and the cut section of the aortic
wall is then removed and the aortotomy is covered with a finger. In a
final step the deployment tool is inserted into the aortotomy and the
clips are released in an automated fashion by rotation of a knob at the
end of the deployment tool. This complete proximal anastomosis system
was cleared by the FDA using a single individual clip as the predicate
(U-Clip) without the requirement for clinical trial data.

The PAS-Port^®^ Proximal Anastomosis system is differentiated from the
above listed devices by the fact that it is an integrated device that
allows the surgeon to create the aortotomy and the implant deployment in
one continuous rotation of a knob. In addition, the PAS-Port^®^ implant
is made of 316L Stainless Steel and the graft loading process has been
designed to minimize graft handling and potential for graft damage prior
to attachment to the aorta.

7.  **MARKETING HISTORY**

The PAS-Port**^®^** System has been marketed in Europe since March 2003
and in Japan since January 2004. As of February 2005, Cardica has
successfully placed approximately 1900 PAS-Port**^®^** Systems in
distribution since market release.

A multi-center, patient registry for the PAS-Port^®^ System was
conducted in five centers in Europe, which reported data on 95 patients
implanted with 123 PAS-Port^®^ devices between April 2003 and March
2004. The registry was designed to collect information on the
performance of the delivery system during the formation of the
anastomosis and also included a short--term clinical follow-up to assess
for any device-related adverse events. There were no defined exclusion
criteria; therefore, this registry was conducted in a patient population
with significant underlying coronary artery disease, co-existing cardiac
conditions, previous coronary interventions or surgery, and other
comorbidities. There were no reports of re-operation for revision or
bleeding associated with a PAS-Port^®^ proximal anastomosis. Average
clinical follow-up in these patients was at six months following
surgery. Patients demonstrated a stable post-operative course with no
patient mortality related to the PAS-Port^®^ System and a low incidence
of device-related adverse events.

Gummert et al from the Herzzentrum Leipzig in Germany will be presenting
data at the 2005 annual meeting of the [International Society for
Minimally Invasive Cardiac
Surgery](http://rds.yahoo.com/S=2766679/K=ISMICS/v=2/SID=e/TID=DFX5_30/l=WS1/R=1/SS=17896360/IPC=us/SHE=0/H=0/SIG=11a4rgg2k/EXP=1110122121/*-http%3A/www.ismics.org/)
describing results from a single center, prospective, randomized
clinical trial in which the PAS-Port^®^ Proximal Anastomosis System is
compared to hand-sewn anastomoses in patients requiring coronary artery
bypass. The primary outcome variable in this study is one year graft
patency assessed by computed tomography (CT). Fifty-one patients were
enrolled in the PAS-Port^®^ treatment group and forty-six patients were
enrolled in the hand-sewn anastomosis treatment group. Five patients in
the hand-sewn group were converted to a PAS-Port^®^ anastomosis due to
presence of severely calcified aortas, which prevented clamping of the
aorta to perform a hand-sewn proximal anastomosis. To date, 22 patients
with PAS-Port^®^ anastomoses have been evaluated by CT at 1 year
resulting in a 100% 1-year patency rate.

8.  **POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**

    1.  *General risks associated with CABG surgery*

General risks associated with performing a proximal anastomosis using
conventional hand-sewn techniques include release of emboli resulting
from aortotomy or clamping of the aorta; (neurological injury from
emboli occurs in approximately 4% of CABG patients). Additionally, veins
may become damaged during the preparation process which may result in
chronic intimal hyperplasia leading to narrowing or occlusion of the
graft vessel. Chronic changes in the anatomy of the vascular wall of a
vein are a normal occurrence as a result of the vein being subjected to
systemic pressure. Lastly, inter- and intra-individual variability in
patient anatomy and surgeon skills in creating a hand-sewn proximal
anastomosis can influence the anastomosis quality.

2.  *Risks specific to the PAS-Port^®^ device*

There have been no product specific risks introduced with the use of the
PAS-Port Proximal Anastomosis System. The overall adverse event rate in
the clinical trials of the PAS-Port Proximal Anastomosis System compares
favorably to published data on patients following placement of hand-sewn
saphenous vein graft anastomoses. The reported incidence of permanent
neurological injury (stroke) seen in the clinical trials was below 1%.
Additionally, there were no device-related re-operations required for
bleeding or graft revision associated with a PAS-Port^®^ anastomosis.
Data from marketing feedback on distributed product continues to support
these favorable results.

9.  **SUMMARY OF PRE-CLINICAL STUDIES**

    1.  In Vitro Product Testing

The PAS-Port**^®^** System was subjected to a rigorous set of in-vitro
testing, which included comprehensive performance testing designed to
ensure that the delivery device and implant met all functional
requirements and performance specifications. This testing demonstrated
that the PAS-Port**^®^** System met the product design specifications
and is safe and effective for its intended use.

2.  Animal Testing

The PAS-Port**^®^** System was subjected to in-vivo testing and results
demonstrated that the PAS-Port**^®^** System performed proximal
anastomoses with long-term outcomes at least as good as those obtained
using standard hand-sewn techniques in the selected model and
successfully met the criterion for the study.

3.  Biocompatibility

The PAS-Port**^®^** System is comprised of a delivery device identified
as *limited contact duration (\<24 hours), circulating blood contact,
externally communicating device* and an implantable clip.
Biocompatibility testing methods of body-contacting and implantable
materials for the PAS-Port**^®^** System were determined in accordance
with ISO 10993-1, *Biological* *Evaluation of Medical Devices,* and
applicable subparts. All materials used in the manufacture of the
PAS-Port^®^ System have been demonstrated to be biocompatible in that
they are non-hemolytic, non-pyrogenic, nontoxic, non-thrombogenic,
non-sensitizing, non-irritating, and biologically compatible for their
intended use. In addition, Stainless Steel 316L is a material safely
used in other marketed circulating blood implant devices, therefore,
subchronic toxicity, genotoxicity, implantation, chronic toxicity, and
carcinogenicity has previously been established for this material.

> []{.mark}

All test samples were processed in the same manner as finished product
and sterilized using gamma irradiation. The biological tests were
performed by independent laboratories following Good Laboratory
Practice.

> []{.mark}

4.  Sterilization

The PAS-Port**^®^** System is sterilized via cobalt 60 gamma irradiation
with a minimum sterilization dose of 25 kGy. A Sterility Assurance Level
(SAL) of 10^-6^ (whereby probability of sterilization failure is less
than one in a million) is maintained. Dose audits of bioburden and
sterility tests are conducted quarterly as required by standard. The
sterilization facilities are certified for Radiation Sterilization
Services in accordance with EN 552:1994 *Sterilization of Medical
Device - Validation and Routine Control Of Sterilization By
Irradiation*, and ISO 11137:1995 *Sterilization of Health Care
Products - Requirements For Validation And Routine Control - Radiation
Sterilization*.

5.  Packaging and Shelf Life

The PAS-Port**^®^** System is sold individually or in "five-packs" and
contains the delivery device and accessory tools. The packaging is
designed to protect the device and accessories against inadvertent
damage and to facilitate placement in the sterile field. The
PAS-Port**^®^** System is placed in a set of trays, sealed in a pouch,
enclosed in a carton, and then enclosed in a corrugate cardboard box for
shipment and currently holds a 21-month shelf-life.

10. **SUMMARY OF CLINICAL STUDIES**

Patients were enrolled in two separate clinical trials between June 17,
2002 and February 6, 2004. Both multi-center, prospective,
non-randomized trials were conducted using protocols that had the same
endpoints for evaluating safety and efficacy and the same follow-up
schedule through six months. The studies were conducted at five sites in
Europe, two of which enrolled patients in both clinical trials.

The clinical study population screened for enrollment in the two
clinical studies consisted of patients referred to the investigator for
multi-vessel coronary artery bypass grafting. Key study inclusion
criteria included age \> 18 and \< 85 years, ejection fraction \> 30%,
creatinine of less than 200 mmol/L and the requirement for non-emergent
bypass of at least one coronary artery. Exclusion criteria were previous
CABG surgery, the preoperative need for an intra-aortic balloon counter
pulsation, bleeding diathesis, a recent cerebrovascular accident and
patients in NYHA IV.

Ninety-seven evaluable patients were successfully implanted with 109
PAS-Port^®^ implants and discharged from the hospital. All patients who
were not successfully implanted with the PAS-Port^®^ device were
successfully converted to a hand-sewn anastomosis without compromise to
long-term outcome. There was a low incidence of peri-operative adverse
events. None of the patients required a re-operation for complications
associated with the PAS-Port^®^ anastomosis, such as bleeding or early
graft occlusion.

Clinical follow-up at three months was available on 94 PAS-Port^®^
implanted patients (96.9%), at six months on 90 PAS-Port^®^ implanted
patients (92.8%) and at twelve months on 88 PAS-Port^®^ implanted
patients (90.7%). The original protocols called for follow-up at three
and six months. The protocols were later amended to include a one or two
year follow-up evaluation in order to meet FDA requirements for long
term follow-up. Index graft patency was assessed angiographically prior
to discharge and again at six months post-procedure. Angiograms were
performed by the treating hospital. Copies of the angiograms were sent
to a CORE laboratory for independent analysis and patency determination.
Patency, per FDA guidance, was defined as freedom of \>50% stenosis or
occlusion.

[]{.mark}

> The six-month angiographic patency rate in evaluable patients
> implanted with the PAS-Port^®^ Proximal Anastomosis System exceeded
> 80% with 95% confidence at six months. Major adverse cardiac event
> rates remained low throughout 12 to 24 months of follow-up.
> Additionally, 93.6% of the patients evaluated at the long-term
> follow-up were negative for any evidence of myocardial ischemia.
> Patients with PAS-Port^®^ index grafts have shown long-term stability
> of their clinical course. At 12 and 24 months, 99% of patients
> evaluated at six months and 100% of patients evaluated at 12 or 24
> months were classified as NYHA I or II. The majority of patients
> (82%), were treated with Aspirin only. There were no reports of any
> device-related patient death, revascularization procedures,
> significant stenoses or occlusions in any index grafts at the
> longer-term follow-up.

11. **CONCLUSIONS DRAWN FROM STUDIES**

In conclusion, the PAS-Port^®^ Proximal Anastomosis System manufactured
by Cardica, Inc. is secure, reliable, and effective for the treatment of
patients undergoing coronary artery bypass grafting as evidenced by the
low incidence of device related adverse events and a six-month index
graft angiographic patency rate which exceeds the criteria of 80% with
95% confidence. 

12. **PANEL RECOMMENDATION**

13. **CDRH DECISION**

14. **APPROVAL SPECIFICATION**