Microsoft word - lit-0014 rev a european clinical report white paper.docx
A Study to Evaluate the Safety and Performance of
ArterX™ Surgical Sealant in Sealing Synthetic Arterial Grafts.
Intra-operative bleeding from the suture lines after the implantation of synthetic vascular grafts can result in extended operative times to ensure the anastomosis is adequately sealed prior to the patient being closed. Synthetic grafts, particularly PTFE grafts are prone to leaking since the graft does not close back down around the suture hole after the suturing needle has been passed. The widespread usage of Plavix (clopidogrel) in current surgical practice has introduced new complexities to the management of these anastomoses after clamp release. Plavix was introduced in Europe in 1998 and is a very effective anti platelet aggregator. It is prescribed widely for those in poor cardiovascular health, who are susceptible to thrombosis leading to stroke or myocardial infarction. Pre-existing blood thinning agents used peri-operatively could have their effects reversed through the administration of protamine sulphate at the end of the surgery. This drug restores the clotting function of the blood, minimizing suture hole leakage at the anastomosis. There are no reversal agents for clopidogrel that can be administered to return the blood to its normal coagulation profile. The most often used method for achieving hemostasis at the anastomosis is compression. Recent clinical studies have shown these types of surgeries to show immediate sealing around 20% of the time, and for approximately 70% to be sealed 10 minutes after clamp release. The benefit of using ArterX Surgical Sealant is the achievement of adjunctive hemostasis in the anastomosis of vessels. The sealant is applied over the top of a suture line to prevent the leakage of blood from the anastomosis when the cross clamps are released and systemic circulation is re-established.
Tenaxis Medical, Inc. has designed and developed ArterX Surgical Sealant based on the relevant European standards. ArterX Surgical Sealant meets all these requirements. The design history for the ArterX Surgical Sealant has been documented in its Design History File.
ArterX Surgical Sealant is a two part sealing agent delivered via a 2 barrel syringe. The two liquids are mixed in a multi element mixing tip and delivered to the application site where they gel. The gelation process forms a flexible adherent layer that bonds covalently to the tissue surface. It will also adhere to a synthetic graft or patch, sealing the suture line and stopping blood leakage from this area. The gel is resorbable. One component is predominantly albumin (bovine serum albumin) and this is crosslinked by the other component, a thermally modified glutaraldehyde (polyaldehyde), treated to minimize the tissue's inflammatory response. ArterX Surgical Sealant will work in a bloody or dry environment. ArterX Surgical Sealant will crosslink and involve blood proteins in the gel matrix with the albumin, and will crosslink this to the amine groups in tissue proteins, forming one soft, flexible composite biomaterial that will biodegrade over time.
The ArterX package consists of the syringe assembly with two identical applicator tips. The second tip may be used in the event that sealant delivery is required at more than one surgical site or the tip becomes clogged.
Tenaxis Medical, Inc. 2. Protocol
The objectives of the study were to evaluate the safety and performance outcomes of the ArterX Surgical Sealant, a resorbable sealant designed to seal the suture holes and prevent blood leakage in native tissue to synthetic graft anastomoses.
This study design was a prospective, multi-center study of prophylactic sealing of suture lines at the anastomosis between native vessel and synthetic vascular grafts using ArterX Surgical Sealant. The study design required >30 patients to be enrolled.
The primary objective of this study was: to evaluate safety and performance of the prophylactic application of ArterX Surgical Sealant device to achieve hemostasis around synthetic vascular grafts used in the open surgical repair of arterial vessels, or for the creation of hemodialysis access.
The primary endpoint was immediate suture line sealing upon clamp removal, as evidenced by a lack of clinically significant bleeding. A minimum of 50% of the anastomoses were expected to be sealed immediately. Active bleeding at time zero is considered a failure.
The secondary endpoint was: Time to secession of bleeding, measured at intervals of 1, 3, 5, and 10 minutes after clamp removal. A minimum of 80% of the anastomoses were expected to be sealed 10 minutes after clamp removal. Beyond 10 minutes is considered a failure.
Provision was made to record device malfunctions as a safety endpoint. In hospital adverse events were tracked and patients were interviewed 6 weeks and 3 months post procedure to determine whether additional adverse events had occurred outside the hospital.
3. Investigational Plan
Two different graft materials were used (Dacron & PTFE) in a number of different procedures. Aortic abdominal aneurysms, femoral, popliteal, tibial and carotid arteries were treated, with either grafts or patches being placed. Patients requiring the implant of PTFE grafts for hemodialysis access were also enrolled.
Each suture line was treated with the sealant while the vessels were still clamped. Clamps were removed 2 minutes after the application of sealant had commenced. Since most applications took around one minute, this approximates one minute of "waiting time". During this waiting time, surgeons were encouraged to free the clamps from sealant, so that clamp removal did not disturb the gelling sealant.
Observations of the suture line were made periodically to see if there was any evidence of blood leakage. These observations were made at clamp release (t=0), then at 1, 3, 5 and 10 minutes after clamp release.
Bleeding status was classified into 4 different categories
If bleeding grades of "1" or "2" were not observed upon clamp release (t=0), the treatment was considered a failure.
The secondary endpoint, time to cessation of bleeding, was considered a failure if bleeding grades of "1" or "2" were not observed at ten minutes (t=10).
Tenaxis Medical, Inc.
This study was also designed to evaluate the safety of ArterX Surgical Sealant. The safety evaluation included adverse events reported. Adverse events were recorded over the course of the study. All patients treated were included in the summaries of adverse events. Each event was summarized by severity and the nature of its relationship to the study treatment.
The demographic composition and breakdown of surgical procedures and graft materials are given in Tables 1, 2 and 3.
Table 1: Distribution of Patients by Age and Gender Table 2: Number and Percentage of Patients and Sites by Surgical Procedure in Intent-to-Treat Category By Pass Graft AV Access Graft Arteriotomy Patients (n) Percentage (%) Suture Sites (n) Percentage (%) Table 3: Number and Percentage of Patients and Sites by Graft Material in Intent-to-Treat Category Patients (n) Suture Sites
This Study was designed as an intent-to-treat analysis. No special data handling conventions were used for subjects who enrolled in the study but were not treated. A total of 56 sites in 32 patients were treated and are included in the intent-to-treat analysis.
Tenaxis Medical, Inc.
Achieving immediate sealing at the restoration of full systemic blood flow on the release of clamps was considered to be the primary endpoint. This was analyzed both with the assumption either that oozing at t=0 was a success or oozing at t=0 was a failure. The secondary endpoint was the time taken to actually seal if immediate sealing was not achieved. If sealing was not achieved by t=10 it was considered a failure. Observations were made at 1, 3, 5, and 10 minutes after clamp release to determine the bleeding status.
Table 4: Sites Achieving Sealing by Procedure Intent-to-Treat Sites at T=0 Minutes Table 5: Sites Achieving Sealing by Procedure Intent-to-Treat Sites at T=10 minute Table 6: Sites Achieving Sealing by Graft Material Intent-to-Treat Sites at T=0 minute Tenaxis Medical, Inc. Table 7: Sites Achieving Sealing by Graft Material Intent-to-Treat Sites at T=10 minute Table 8: Secondary endpoint - Times to Sealing by Procedure - Number of Sites Evaluable Sites Table 9: Secondary endpoint - Times to Sealing by Graft Materials - Number of Sites Evaluable Sites 5. Conclusion
ArterX Surgical Sealant was demonstrated to be safe and effective in this study when used for prophylactic sealing of synthetic graft to native tissue anastomoses in a broad range of surgical procedures. Plavix (clopidogrel) is a very effective pharmaceutical agent used to reduce the risk of thrombosis in patients with cardiovascular and peripheral vascular disease. Its widespread use has resulted in bleeding problems in patients undergoing surgery. The ArterX Surgical Sealant could be very useful when prophylactically applied over the suture line before clamp release in patients undergoing any form of surgery employing synthetic, native vascular grafts and patches. At worse case when oozing is considered a failure, this study demonstrates that over this 32 patient series - 92% success was achieved in immediate sealing. Also when worse case is considered, secondary endpoint had an overall success rate of 98% when oozing is considered a failure. There were no device related adverse events. Most importantly in regard to anaphylaxis or immunologic response, sensitization testing that was conducted as part of the ISO 10993 package for ArterX
Tenaxis Medical, Inc.
sealant and found no evidence of immunologic reaction with the use of ArterX Surgical Sealant. In addition, no animals were observed to experience anaphylaxis after exposure to ArterX Surgical Sealant among sensitization study test animals or among the large animals treated for safety and effectiveness during preclinical testing. These animal data are supported by the clinical findings to date. The most modern alternate products available that have similar applications have shown efficacy rates of around 50%. Lumsden et al showed the Omnex product to be 55% effective in the immediate sealing of the anastomoses of synthetic grafts in femoral - popliteal bypass procedures and grafts for hemodialysis access. Glickman et al showed the CoSeal product to be 47% effective in immediate sealing in similar applications. Coselli et al showed BioGlue had an immediate sealing efficacy of 61% in a less challenging application, native artery - to native artery anastomoses. ArterX Surgical Sealant offers the potential to reduce the time that patients spend under general anesthesia and reduce the volume of blood products that they receive post surgery. Its superior clinical performance characteristics and safety profile show that ArterX will improve surgical outcomes while reducing the risk. ArterX Surgical Sealant offers a very safe and effective alternative to the current standard of care. 6. Bibliography 1. Lumsden AB & Heyman ER. Prospective randomized study evaluating an absorbable
cyanoacrylate for use in vascular reconstructions. J Vasc Surg 2006, 44: 1002-1009.
2. Glickman M., Gheissari A., Money S, Martin J., & Ballard J.L. A polymeric sealant inhibits
anastomotic suture hole bleeding more rapidly than gelfoam/thrombin. Arch Surg. 2002 137:326-331.
3. Coselli JS, Bavaria JE, Fehrebacher J, Stowe CL, Macheers SK & Gundry SR. Prospective
randomized study of a protein-based tissue adhesive used as a hemostatic and structural adjunct in cardiac and vascular anastomotic repair procedures. J Am Coll Surg 2003; 197:243-253.
Tenaxis Medical, Inc.
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