Angiolink`s Staple-Mediated VCD Addresses Limitations of Current Technology Part II

We designed the staple with a surgeon’s mentality, and chose titanium as the metal. Titanium is a very cheap, very inert metal that actually is what surgeons will implant most of the time with heart valves and with hip replacements. The staple is a very small, low-profile 3-mm staple. Figure 2 is really 3 millimeters, and portion A is designed to sit above the artery. The B portion is designed to actually implant into the outer walls of the vessel, avoiding the lumen of the vessel. This VCD is totally extraluminal in its action, which is one of its major advantages. Closing the Vessel from the Outside When we do coronary bypass surgery, when the heart is beating, we will put a tube in the aorta the size of a thumb. In order to do that, we put a suture on the outside of the aorta with little pledges, and then as soon as we pull the tubing out, we tie the suture. This is the classic purse string suture, which is used hundreds of times a day in cardiac and vascular surgery, and is the same concept we want to develop in the cath lab to close vessels from the outside. The EVS staple is designed to open, expand, move forward and grasp tissue just the way a surgeon would suture around the vessel outer wall (Figure 3). In the OR, the purse string suture is then tied down over the arteriotomy, closing it from the outside and avoiding narrowing of the vessel lumen. The current staple design will open to accommodate a 15 Fr arteriotomy, but can be designed for closing smaller or even more exciting larger holes, so this device has the potential of closing all of the larger sheath-based technology coming on the scene. You pull the trigger and a little plunger makes the staple open; it expands and it purses (Figure 3). Again, we call this a purse string effect and what it gathers is the femoral sheath, the adventitia and the media of the vessel wall, which are the outside layers, not the inside, meaning no narrowing, no injury, and no thrombosis. The Angiolink closes the arteriotomy in one single pull of the trigger. The staple device is also sterile and loaded in a separate delivery system. Figures 4-5 are from a bovine model, and are magnified, showing the arteriotomy viewed from inside the vessel. You can see what the device looks like in a bovine artery, and what the outside and inside of the artery look ike with multiple closures. Again, there are no endoluminal components, and no narrowing of the lumen. The device basically closes everything from the outside in. Figures 6-8 show the current device, but there is also a newer design, a second generation, which will be the one that will probably go on the market if FDA approval is given (or it will be available soon thereafter). The second generation device can be deployed via the existing case sheath and not via an introducer sheath. At this time, the device has a 3-step introducer. When we first got involved with the device four years ago, there were 18 steps; it drove you crazy. It’s not easy to design a staple VCD, so we’ve gone though a lot of technical changes to make it happen. You will localize the artery lumen, similar to what needs to occur with a Perclose® device (Abbott Vascular Devices, Redwood City, CA). A bleed-back port allows you to localize the vessel. You have to stabilize the anterior vessel wall with the introducer step. The whole question here is, if you’re going to bring something down from above, how do you localize the arteriotomy and how do you stabilize it? Through the introducer system, we are able to stabilize the anterior wall and then bring in the completely sterile staple with the trigger-released staple mechanism. Staple Sterility: No Infection Since the staple is completely sterile until deployed at the artery level, we’ve removed infection from the whole process. You don’t think of stents getting infected, because they really and truly don’t. That’s because they are inert metal, inserted completely sterile to the level of the artery. Collagen, sutures, etc., if they are flipping around on the wound, may increase the risk of infection. One of the reasons we designed the inert staple-mediated VCD was to address the complex infection issue. How Does the Device Work? The staple is loaded into the introducer sheath above the artery; you pull the trigger and the staple opens, expands, grasps the femoral sheath above the artery, the adventitia, and then the media and this closes the arteriotomy, all with a single trigger pull. Figure 9 is the arteriotomy, shown closed as a slit between the pledget-like arms of the staple. You can see little nitinol filaments which we call the feet that stabilize the anterior vessel wall. As you pull the trigger, the introducer system gives you the anterior wall support that you need. Then, with the last release of the trigger, the nitinol filaments straighten out and pull out of the wound immediately, just as the staple is deployed. The following describes a typical case. Once you have done the case and have your introducer sheath in place, you go ahead and go down, and localize the vessel lumen over the wire. (There is another, more mature generation device that will eliminate 1-2 steps.) Next, you localize the vessel itself, witnessed by back bleeding via the lumen localization port. (The next-generation device will not have this introducer; it will go through the existing case sheath.) The introducer has 3 steps. You then remove the first part of the introducer sheath. You’ve stabilized the anterior wall. The staple now comes in localized to the anterior wall and you will simply pull the trigger. In the pivotal trial, staple deployment takes less than one minute. Our cath lab technologists are far better than our physicians at deploying this VCD. They routinely do it in about 45 seconds. The idea here is to get immediate, secure, mechanical closure. In the pivotal trial, we held manual compression (MC) for one minute, just as is required in most other FDA-approved VCD trials. There can be a little bit of track oozing, just like anything else. We use this device in large sheaths, anticoagulated patients, IIb/IIIas, etc. Our goal has been to try to design a VCD that is going to address many of the limitations of the current VCDs. The Surgical Perspective What does the staple look like in the body itself? Figure 10 is the first patient where we exposed the staple after immediate deployment in the OR, in a patient requiring an angiogram immediately before AAA exclusion. Figure 10 shows the sheath track. You always hear that the sheath track is oozing, etc. Very interestingly, here is the first photo ever taken anywhere of a sheath track which is about 10 minutes old. Figure 10 is what the track looks like after we pulled the sheath out and we’ve cut down to the vessel. Now we dissect down, and Figure 11 shows the staple just anterior to the artery. We gathered the femoral sheath and the patient’s own tissue, and used it to close the arteriotomy with the adventitia of the vessel. The series of figures 12-18 (figures 12-13 are on page 18) shows the case of a patient with a 6 cm AAA, where we performed a 6 Fr-based angiogram and immediately exposed the staple after vascular closure. The introducer sheath is inserted (Figure 12), the vessel lumen is localized by the back bleed (Figure 13) and the sterile staple is deployed (Figure 14), then 45 seconds of light pressure is applied (Figure 15) and complete hemostasis is achieved (Figure 16). Figure 17 shows 2 minutes later. We cut down on the femoral vessel to exclude the AAA through a small arteriotomy, but we wanted to evaluate the staple results. We utilized these surgical opportunities to expose the femoral vessels in the OR, and designed this surgical staple to be delivered percutaneously, with the goal of decreasing femoral artery complications after percutaneous procedures. Figure 18 shows the staple on top of the artery. Figure 19 shows the low-profile 3mm titanium staple under magnification, after removal and before AAA repair. Safe (Despite the Stick) Figure 20 is a patient in the OR. We did a purposeful high stick. If you stick the SFA or the profunda, or the external iliac artery, you can’t safely use any other VCD. Since this staple is extraluminal, it won’t narrow the vessel. The closure should be secure; therefore, these non-common femoral artery (CFA) sticks are not a contraindication to use the staple. We’ve designed the EVS staple in the hopes of addressing this limitation of the current VCDs. It’s not that the current VCDs aren’t good and that they don’t work, but that they don’t work in enough patients. Our goal is to expand the use of VCDs to all patients by designing the ideal VCD platform, which we believe is a staple. Figure 21 shows the CFA. You can see us actually pulling down and bowing the vessel. The inguinal ligament is above the vessel, and you can see the staple underneath the inguinal ligament. We pull the CFA and staple down. The profunda and SFA are below. This is the external iliac, so this is a purposeful high stick. Again, we’re not experimenting or playing games here; we’re going to fix the AAA anyway. However, this OR experience has helped us design the staple to work. The staple would have given us immediate, secure closure in a high stick femoral access at high-risk for complications with closure, using any other VCD or even manual compression (MC). In Figure 22, you can see a bifurcational stick in 4 mm vessels. You don’t want to close this stick with any of the current mechanical devices, because it will be high-risk for thrombosis. Figure 23 is an SFA stick. Again, this is something that this staple device will allow us to close but should not be closed with existing VCDs. We have successfully deployed the Angiolink staple in patients with non-CFA sticks, PVD, and small vessels (1-2 One of the frequent questions we hear is, Wait a minute, doc, you’re leaving metal in there. Is that going to be a problem? Well, you can look at that a couple of different ways. We often leave a larger piece of metal, as long as your forearm, in the SFA. We certainly leave a lot of metal all over the body and often deploy surgical staples on or near vessels without problems. We don’t think a 3 mm piece of inert metal should be of that much concern, but we do have a strategy to address this issue. Figure 24 (page 22) shows how small the staple is as an access needle is inserted into the CFA above a previous staple closure case. Figure 25 (page 22) shows the sheath in place. The procedure was performed without complications. The staple may actually be an advantage for re-access because when you re-enter, you see it on fluro as a target and thus know where to stick during reaccess. The staple’s conformational change will not allow you to go through the center of the staple. We don’t have a wealth of data regarding re-access with this device, nor on when you can re-access with any other device or even after MC, so there are still some unanswered questions. The point is that we’re working our way towards developing a VCD that will allow safe, immediate re-access. Figures 26 through 29 (page 22) are from an abstract we presented at TCT 2003.1 The abstract described using the Angiolink device in what we call the high-risk stick patients or those with PVD, high stick, low SFA-profunda sticks and small vessels. In other words, these 49 patients were closed with the Angiolink where no other current VCD would work. Certainly, if we have a VCD that can work on this high-risk subset of patients, it ought to be applicable to every case in the lab sort of a one-stop shopping for a VCD. Figure 26-27 shows the data we’ve reported and the 49 patients we treated, with mostly 7-8 Fr closures. Most of these cases were interventions with very high use of anticoagulation and IIb/IIIa agents. There is very little published data on any device used in this high-risk patient subset. VCDs were really first designed for patient, as well as hospital, convenience. This is fine, but this manner of thinking only scratches the surface potential of VCDs. We’re trying now to move VCDs into the realm of treatment, as well as case planning and management, which we will comment on further. Our procedure success rates were > 96%. All cases stopped bleeding within 2 minutes (Figure 28). In general, all patients were on Plavix, aspirin, and IIb/IIIas. In this high-risk subset of patients, we achieved ambulation of well over 90% in less than 3“4 hours. Now we have learned to even ambulate earlier. In the Angiolink pivotal trial, we now have consistent ambulation in less than 1 hour. As we learn more about this device, we can use it in high-risk patient populations and extend its use even further. No major surgical complications occurred in this high-risk group (Figure 29). A few minor hematomas occurred; all of which were less than 3 cm. We followed all of these patients with ultrasound at one week and found that no pseudoaneurysms, staple fractures or migrations occurred. The Angiolink Pivotal Clinical Trial The Angiolink Pivotal Clinical Trial, a 360-patient trial, was completed in December 2003. The trial is being put in abstract form, and results will be published and announced at the TCT 2004 meeting by Dr. Gary Ansel.³ The trial was randomized between MC and the Angiolink staple, and was a FDA-guided trial with the goal of receiving FDA approval for femoral arteriotomy closure. The first 240 patients were unlocked several months ago, which is what happens about half way through a trial. The data is then analyzed and in that way, if data is bad on either side, then the trial can be stopped, etc. In this case, the randomization showed no major complications from the Angiolink staple, so the trial was allowed to continue. This trial will be one of the only VCD trials performed that will show this device as having significantly less major complications than MC. Other VCD trials have shown the VCD to have more complications than MC.⁴ We have experience with over 400 Angiolink deployments performed in Paraguay. This is where Angiolink did a lot of its original work with different device prototypes. In other words, earlier four-, five-, or six-step device prototypes were used and even after doing a meta analysis and analyzing all of those patients, over 95% procedural success rates were obtained. We have never had a surgical complication with this device, because when and if it fails (and we believe it fails safely) all you have to do is hold pressure. In other words, you convert the rare failure to traditional MC because you’re not inside the vessel, you’ve not torn the vessel, you’ve not thrombosed it, you did not hit the back wall, and you’re not going to get infected. If there is a failure, you will immediately recognize it (it’s not hidden). You then hold pressure, and all that remains is a 3 millimeter piece of titanium, sitting 3-4 mm above the anterior wall of the artery. It has gathered some autogeneous tissue and will probably even facilitate MC, like some of the other devices. If you’ve seen the patient’s legs when we do heart surgery, you may remember that the patient has more staple clips up and down the legs near the vessels than stars in the sky, so leaving a little piece of metal in this location should not be a major problem. We can’t emphasize the fails safely mode or removal of infection from the overall VCD-use equation enough, because through the years, one of the biggest problems with the current VCDs is the unfortunate occurrence of catastrophic complications. Reported catastrophic complications have included: Femoral artery thrombosis or VCD-component embolization requiring major surgical procedures; Delayed major bleeding complications due to unrecognized closure failures (massive late bleeds, pseudoaneurysms, retroperitoneal hematomas, etc.) Severe infections. These are very costly failures, both clinically and economically, and have resulted in significant morbidity and mortality for the patients. Limb loss and even deaths have been reported and when a lab, hospital, or physician experiences one of these catastrophic complications, it is easy to see why the facility and physicians may just stop using closure devices all together. We can even remember a medical device advisory (MDA) warning issued by the FDA which reported complications related to VCD including hematoma, retroperitoneal bleed, pseudoaneurysm, late bleeding and infrequently, death.⁵ Learning Curve We think one major advantage of the Angiolink is that it is very simple to learn and use. In the pivotal trial, you have what’s called roll-ins, which means getting the physicians in the trial to learn to use the device, since it is new. Unbelievably, when we put this device in the hands of our operators at the multiple centers (about 10 different centers), after an average of only 2.5 deployments, all the doctors wanted to immediately use it on cases. The roll-ins, or learning curve, had been designed to be 10 deployments, but after just 2 or 3, physicians said, We don’t need any more training. There is a very minimal learning curve on this VCD because the device works, it is simple, it makes sense, it localizes the vessel, and all you have to do is pull the trigger. In our experience and in the experience of the trial, the entire closure often takes only 1-2 minutes to complete and can be performed by the cath lab staff. Another important advantage is that the staple is very inert. We know this about titanium because of its long surgical history. The device has no collagen, braided sutures or other reactive foreign components, and so it should be very biocompatable and non-reactive. When we cut down on a staple that’s been put on an artery for 1-3 weeks or longer, you don’t see all the scar tissue that you see with MC and the significant scar you see with the other VCDs when exposed in the OR. We have a very long surgical history with titanium; we know it is biocompatable, inert, and is very safe. Ultimately, a Treatment Tool The Angiolink staple has the potential to be very cost effective. Titanium and plastic are very cheap. Now, we’re not the company, so we’re not sure what this device is going to cost, but the bottom line is that we know that it’s made from a very cost-effective component, therefore, when cost becomes an issue this device should be very competitive, if not less expensive. Since the staple is completely sterile until deployed at the arterial level, we think there’s going to be less infections, less catastrophic problems and this device should have infection rates just about like a stent. This is a major advantage. We don’t even consider infections when deploying stents because it is so rare. Diabetes and obesity have been considered risk factors for VCD infections, and IV antibiotics are often used with VCDs in these patients because of infection concern. The elimination of infection has huge implications. Large PCI trials have shown a 20-25% incidence of diabetes, and diabetes is even more prevalent in PVD (40-50%). We’ve seen it in 80-90% of our patients with infrainguinal disease, especially with critical limb ischemia (CLI). What a huge advantage it would be if this device can decrease infectious VCD complications. There are no endoluminal device components left behind, therefore, you’re not going to narrow the vessel, you’re not going to injure the back wall and you’re not going to embolize anything, therefore this device has the potential to eliminate arterial thrombosis. Since it is extraluminal and has no endoluminal components, the staple can be utilized in vessels of any size (Future Generations What about the device in the future? You say, Well, doc what about the metal? Is the metal going to cause problems? We already have a precedence analogy, with bioabsorbable staples made of vicryl, which are used today in many surgical applications. Vicryl is an absorbable polyglycolide and it’s gone in 30-days and often are permanent; these are not considered to be a problem. A Radical Revolution and a New Standard of Care In the 1960’s and 1970’s, a staple was considered radical by the surgical community, but the staple platform has helped to totally revolutionize all surgical specialties. The staple is a cornerstone of all endoscopic and minimally invasive techniques. In the 1970’s and 1980’s, a balloon and metal stent was also considered radical, but likewise, they revolutionized all of cardiovascular care. These two innovations are responsible for why we are sitting here today. As radical as a metal staple VCD may seem today, we can envision this platform potentially revolutionizing what we do both today and in the future in the cath lab, analogous to what the staple did for surgical therapies. This could be the VCD platform that may allow safe, simple secure closure on every case brought into every lab, in every country worldwide, setting a new standard of care.

1. DE Allie, CJ Hebert, MD Lirtzman, et al. A Novel Staple-Mediated Vascular Closure Device: Successful Closure in PVD, Small Vessel Anatomy, and Noncommon Femoral Artery Sticks. Oral TCT, September 15-17, 2003.

2. DE Allie, MH Khan, PS Fail, et al. Novel Staple Mediated Vascular Closure Device Successful Repair of Noncommon Femoral Artery Vascular Access Site STICKS. SCAI’s Annual Scientific Sessions, May 7-10, 2003, Boston, Journal of Catheterization and Cardiovascular Interventions2003;59(1)A-13:96.

3. Ansel G, Sharma R, Fail P, et al. A Pivotal, Prospective Multi-Center, Open-Label, Randomized Study to Determine the Safety and Effectiveness of the EVS Vascular Closure System. TCT abstract, September 27-Oct 1, 2004.

4. Stuart M. An Open Market for Vascular Access Closure Devices. Start-Up: Windhover’s Review of Emerging Medical Ventures. May 2004:7.

5. FDA Medical Device Advisory. Feigal D. Complications Related to the Use of Vascular Hemostasis Devices Oct 8, 1999.