Distal Embolic Protection:A routine part of interventional procedures in the near futureCath Lab Digest talks with Donald S.
Why do you think that distal embolic protection has only relatively recently become a topic of interest in invasive cardiology?
In 1977, before Gruentzig did his first catheter-based angioplasties during bypass surgery, he evaluated for arterial debris by collecting the effluent from an artery dilated during surgery, and looking for embolic particles (none were seen). Clinically, when you look at the literature up through the mid-1990s, the only reports of embolization are in patients with thrombotic lesions, where a chunk of clot breaks off, embolizes and blocks a distal large branch on the angiogram. There was nothing compelling people to think about distal embolization or protection against such embolization. There were, however, some unexplained problems. The two biggest examples are:
1. Elevations of CK after otherwise successful procedures;
2. The no-reflow phenomenon, where antegrade flow in the coronary is reduced and patients have chest pain with ST-segment elevation even though the large vessel is open.
In 1990, we were one of the first groups to suggest that no-reflow might be due to spasm not of the big arteries but of the small vessels.1 We recommended treatment with intracoronary calcium channel blockers like verapamil, diltiazem, and cardipine, which most of the time seemed to improve the flow. However, these drugs didn’t really work in a preventative way. You could give them before an intervention but you might still get no-reflow.
Next, there arose a great deal of interest in the glyco-protein IIb/IIIa receptor blockers to prevent platelet adhesion, with the belief that maybe platelet clumping was causing no-reflow. However, at least in saphenous vein graft interventions, the randomized trials of GP IIb/IIIa inhibitors did not show a reduction in adverse events in saphenous vein grafts.
Finally, the first of the distal protection devices, the PercuSurge GuardWire (actually developed with the hope of preventing stroke during carotid interventions), underwent testing in vein grafts in the SAFER trial.2 The trial showed that embolic debris was being recovered and demonstrated a dramatic reduction in the incidence of CK elevations and no-reflow in saphenous vein graft intervention. There was a 42% reduction in CK elevations, from 16 to 9, and more than a 50% reduction in no-reflow, if I remember correctly, from 8.3 to 3.3.
The SAFER trial really was the turning point where people went from saying, Embolization doesn’t occur why should I worry about it? to understanding that in fact it occurs very frequently, in almost every case with saphenous vein grafts, and protecting against embolization reduces these otherwise unexplained adverse events.
What are some of the ongoing challenges of creating an embolic protection device?
There are 3 classes of device:
1. Distal occlusion. The PercuSurge GuardWire utilizes distal occlusion, which temporarily blocks the flow of blood while the intervention is done. Any debris trapped in a stagnant column of blood can be aspirated before the distal occlusion is released.
2. Distal filters
3. Proximal occlusion. This type of device interrupts the flow of blood upstream of the blockage.
There are pros and cons of each type of device, and I think one of the unsolved questions is which class of device and within that, which device is going to be the best, in terms of deliverability, maintaining flow, recovery of debris, and so forth.
The second big question is, how far can you generalize this model beyond saphenous vein grafts? We chose vein grafts as the initial testing ground, because they had a very high complication rate, and there’s a lot of viable debris. Regardless, whenever people have looked at intervention in other atherosclerotic vessels, be they carotids or renals, people have also found debris, and have shown that embolic protection reduces complications. The same thing probably should hold true for native coronary intervention, because people have certainly shown that debris is released, particularly in acute myocardial infarction (MI) interventions, and probably also in vulnerable plaque/unstable angina-type interventions.
We’re still struggling with demonstrating the clinical benefit of embolic protection. The EMERALD trial, which was just reported at the American College of Cardiology meeting by Gregg Stone, was the trial of the PercuSurge GuardWire in acute MI interventions. Even though the pilot data suggested that it improved outcomes, that was not demonstrated in this big, randomized trial.
My view is that embolization is a common in fact, one could almost say ubiquitous complication of dilating atherosclerotic stenoses in any vessel. The end organ being perfused by the vessel is sensitive to such embolization, which is certainly the case in the brain, heart, and probably the kidneys as well. The incidence of adverse outcomes would be reduced by embolic protection. I believe we’re headed for a situation where embolic protection becomes more of a routine part of intervention, the same way stenting is a routine part of intervention.
Do you feel that embolic protection is still important even with direct stenting?
Oh, yes. You know, we’ve looked at that in the SAFER trial. It’s true that people who got direct stented had a lower incidence of CK elevation, but patients weren’t randomized to direct stenting. When you look at the patients who did get direct stented, they tended to have simpler lesions. Also, patients where direct stenting was tried and failed, were then predilated. Anybody with hard lesions to fix ended up in the predilated group. That explains some of the baseline apparent benefit of direct stenting it was used in simpler lesions. However, there was significant further reduction in adverse events utilizing the combination of embolic protection, even with direct stenting.
This brings up another question that needs to be addressed, namely, should embolic protection (let’s say in saphenous vein grafts) be used selectively? Can you identify lesions that are going to embolize well enough to say, okay, here’s a case where I will use embolic protection, or on the other hand, to say, this lesion really looks pretty good and I’m not going to use embolic protection?
It turned out that we really couldn’t identify any lesions that were so benign that they didn’t have MACE events for that class of lesion, or that events were not reduced by embolic protection. When I speak about this, I say it’s like wearing your seatbelt. You don’t say, well, I’m only going a couple miles, or the weather looks alright, or I’m a really careful driver, so I’m not going to put my seatbelt on today. Basically, you get in the car and you put on your seatbelt. I think that the same approach needs to be taken with embolic protection in saphenous vein graft intervention. The lesions are so unpredictable, and there’s not much you can do about the events, when they happen. If you have a device that’s easy to use and effective in preventing these events, the best approach is to use it in every case.
Can you talk about your involvement with the distal filter-type Rubicon Filter System?
I’ve been working with Rubicon for the last couple of years as an advisor. One of the challenges of the filter devices has been that virtually all of them are held in their collapsed state by an outer sheath as they’re placed across the lesion. The outer sheath means that the device profile, or diameter, is larger, and the device is somewhat stiffer than the PercuSurge GuardWire, which essentially is a balloon on a guardwire. The profile of the current-generation guardwires is between 26 and 29 thousandths of an inch. Most of the filters, with their delivery sheath in place, have a current profile of very close to 3F, which is 40 thousandths of an inch, so most filters are somewhat stiffer than a guardwire.
The Rubicon Filter is unique because it uses a different mechanism to keep the filter closed during delivery. The mechanism is a very thin envelope around the collapsed filter, which is released by pulling a microwire that runs inside the guidewire. The deflated profile of the device is very comparable to the PercuSurge device. The flexibility is very much like a guidewire in terms of crossing a lesion, and the filter can be released by pulling the internal wire, which has really been the main advantage.
The Rubicon Filter is in clinical practice in Europe; it’s been able to go places that no other filter device could navigate through tighter lesions and through greater tortuosity, acting really as a guidewire.
What is going on with the planned Rule-SVG trial?
I think it’s still at the FDA; it’s awaiting initiation in the second quarter of 2004.
There are trials going on in Europe right now?
Yes, the European regulatory path is always much easier. Rubicon is expecting their CE mark in Europe in 2004. The device is really being used in vein grafts and carotids. There’s been some acute MI trials as well and some small registries in Europe. It’s been behaving very well in terms of deliverability.
What type of learning curve does it have?
I think it’s probably the simplest of the embolic protection devices, because there’s really no set up and the guidewire-like device is placed across the lesion as any bare wire would be. Then the center ripcord is pulled to deploy the filter, and the rest of the procedure, in terms of stent delivery, takes place as it ordinarily would. A separate retrieval sheath is used, to recollapse and remove the filter. I think it is probably the most intuitive and simple of the devices.
Do we have any idea (no doubt it varies by device) what percentage of particles get missed by an embolic protection device?
Well, there are two issues to address in terms of missed particles. One issue is particles that go through the holes in the filter, and the other is particles that bypass the device completely, because the device is not completely opposed to the vessel wall.
That would be an operator issue?
Well, it may be a device limitation, or it may be an inability of the device to handle particular features of the lesion. There are devices that tend to pull away from the vessel wall if they’re in a curved segment of the vessel (as compared to other devices that stay opposed to the wall and prevent particles from going past). The EPI FilterWire3, is the only approved filter right now in the U.S., behaves very well. But in the trial with the original or EX design, operators had to be careful to look at the deployed filter in two views, in order to be sure it was opposed to the wall in curved vessels. If it wasn’t opposed to the wall, there were more complications, and that was addressed in operator training. Now Boston Scientific has a second-generation device that’s awaiting approval, called the FilterWire EZ, that tends to be more automatically well-opposed to the wall, a key feature in any distal filter system. The second mechanism of debris loss involves debris passing through the filter pores. This depends somewhat on the size of the pores, which in most devices is about 100 microns. Some of the devices don’t use plastic sheaths with holes, but use nitinol mesh instead. That tends to let some bigger particles through, up to 150 microns in size. The good news is that even the filters with 100-micron holes tend to trap some of the smaller particles as well. Anyway, it turns out that smaller particles are much better tolerated by the distal end organ than are large particles, so those particles that do get through the filters don’t seem to cause much in the way of clinical problems.
You can look at it this way: the size of a white blood cell is 25 microns, so having particles that are less than 100 microns go through is really not an issue. This was really demonstrated in the FIRE trial, which was the pivotal trial that led to the approval of the FilterWire. FIRE compared the FilterWire to PercuSurge. PercuSurge, via distal occlusion, recovers particles of all sizes. The FilterWire was theoretically letting smaller particles through, and yet the trial showed that the degree of protection offered by those two devices was the same. If you really needed to collect every last particle, regardless of size, FIRE should have shown that the FilterWire was inferior, but it didn’t.
One disadvantage of distal occlusion is that the end organ is ischemic during the time the device is in use. In the SAFER trial, the time of occlusion was 4-6 minutes. During this time you are deploying the distal occlusion device, getting the stent in, sucking the blood out of the proximal vessel and deflating the device. If patients didn’t have adequate collaterals, if they were having chest pain, EKG changes, etc., the operators were under a lot of pressure to work quickly. Meanwhile, with the distal filters, flow is maintained, the patient is more comfortable, and the operator is more relaxed.
The Rubicon utilizes a nitinol framework to support a plastic membrane with holes, and the holes are on the order of the 100 micron size. Perfusion is really the main reason why the size of the holes in the Rubicon filter are not smaller to catch more particles, because if you did make them smaller than 100 microns, they would tend to plug up with platelets and fibrants much more quickly. The filters are usually in place for anywhere from 5-10 minutes as the procedure is performed. It’s there longer, but the reason it’s there longer is that the patient is feeling better and the operators aren’t under the gun to work as quickly and let down the distal occlusion device, because flow is being maintained.
What sort of developments should we expect in the future?
The next device approval is most likely going to be the Cordis AngioGuard, which was part of the SAPPHIRE Trial for carotid stenting. The FDA panel has just recommended approval as a combined product the Cordis Precise stent and the AngioGuard system. Cordis may be able to leverage that approval to get approval of the AngioGuard filter for saphenous vein graft use.
Medtronic is involved in the trial of their nitinol mesh filter, and we’ll see, in the next year, a number of other filter devices coming to market. I think we’ll see the Rubicon filter coming to clinical trial and getting to market within that timeframe as well.
The other information that’s going to be interesting is trial results with filters in acute myocardial infarction, to see whether filters actually offer benefit over no distal protection. Remember, in the EMERALD trial, PercuSurge wasn’t able to show that benefit. If you use distal occlusion in the native coronary, there are a lot of side branches that come off the native coronary proximal to the point of occlusion, and by blocking the vessel at the point of occlusion, any debris you liberate gets shunted into those side branches. Protecting the distal vessel by making the proximal branches worse may have compromised the benefit. Whereas if you do the same thing with the filter device, to the extent that flow is maintained, most of the debris will end up being strained into the filter rather than passing into those proximal side branches. I believe that emboli cause problems in acute myocardial infarction intervention. Effective embolic protection will reduce those adverse events and the filters may be more effective in doing that, but those trials probably will be coming out in the next year. It will be interesting to see.
Do you think that the embolic protection devices coming out will facilitate the spread of interventional endovascular procedures?
I think that it will improve the safety and by improving the safety, it will improve people’s comfort and will help expand the use of interventional procedures. If you look back even a few years, the scariest cases that interventionalists used to do were vein graft interventions, because 10% or more would have no-reflow phenomenon they would be ischemic, they’d have infarctions, people would die, and there was nothing you could do for it. Emergency surgery wouldn’t help, because the problem wasn’t a blocked proximal vessel, it was blockages of all of the smaller vessels in the myocardium. It used to be people’s least favorite procedure. Now, with embolic protection, people aren’t even fazed.
Stents have removed one element of what used to be the Russian roulette of angioplasty, which was dissection and abrupt closure with emergency surgery, which has gone down from 3% to 1% to 0.1%, and people are now a lot more comfortable. Drug-eluting stents have substantially reduced the restenosis risk. Now, embolic protection, by reducing the risk of periprocedural infarction and no-reflow, will make people more comfortable and will improve the scope of percutaneous intervention.
Dr. Baim discloses he is a consultant for EPI, Boston Scientific Corporation, and Rubicon Medical.