Microvascular Disease and Injury: Prevention and Therapies

Tim Fischell: Many centers have spent a lot of money on the 25 or so different distal protection devices available today. We are currently preparing a manuscript on a slightly different, simpler, and considerably less expensive approach to vein graft interventions which appears to be about five times more effective than distal protection devices. This approach involves pre-medicating — the VAPOR trial with verapamil involved pre-medicated vein grafts just before direct stenting was performed — you do not perform balloon angioplasty in a vein graft. The pre-medication with verapamil results in very marked arterial or vaso dilatation, followed by direct stenting — preferably with a prolonged balloon dilatation for at least two to three minutes, because that’s as long as verapamil will last. It is for this reason that we have chosen to use nicardipine. Our institution has data on a series of 60 consecutive vein graft interventions in which the patients were pre-medicated with nicardipine. The lesion is wired, which does not cause no-reflow if done carefully, then the guide is loaded with a tip and 300 mcg of nicardipine is injected down the graft. Nicardipine is the most potent calcium channel blocking arterial dilator or vasodilator by a factor of two or three — greater than verapamil and more than cardizem. It causes no negative inotropic or chronotropic effects, no heart block, and no significant hypotension. The 300 mcg injection lasts for approximately six minutes. The stent is immediately placed and the balloon is inflated for three minutes which helps to seal the perfusion balloon — a concept in which all that microvascular stuff is sealed behind the struts, then the balloon is deflated and removed. Out of the 60 cases, there was one asymptomatic CPK bump and zero no-reflow events. This approach saves approximately $1,400 and about 30 minutes per case. Nicardipine and adenosine are put in the flush bag for AngioJet and Rotablator cases. We have performed 175 consecutive Rotablator cases with one slow-flow event. The native circulation in the setting of myocardial infarction, I will concede, is a different animal. The endothelial damage from ischemia, the lack of EDRF, the endothelin release — whatever it is — native vessels with infarcts are very different than vessels we see in elective interventions or vein grafts, and they may be very different than the one Richard showed that was filled with clot. I am talking here about the 80% lesion in the mid-portion of a vein graft. In those cases, we administer nicardipine, stent the lesion, inflate with a balloon for three minutes, and see very pleasing results. Richard Heuser:Tim, that’s a great option which is very similar to what I’m talking about. That is, these devices are sometimes far too complicated. I attended a session at the TCT last year where they discussed PercuSurge complications. We had a unique complication due to a technologist who was unfamiliar with the procedure set-up. The wire was put in backwards — not once, not twice, but three times! It is just not intuitively obvious. The only downside to what you are describing is the issue of big particles. But with that sort of vasodilation, the vascular bed can probably handle it. Tim Fischell: Another very important point involves no-reflow in vein grafts. Fifteen papers have discussed this, and we published a couple of them. These papers showed that no-reflow can essentially be reversed with a number of agents such as repeated boluses of adenosine, verapamil, nitroprusside, cardizem, nicardipine, etc. So what is the etiology of no-reflow in vein graft interventions? You cannot reverse mechanical obstruction of the microvascular bed with vasodilators, which tells us something about the pathophysiology of no-reflow in vein grafts: it’s 90–95% microvascular vasoconstriction and 5% macroembolic. Filters are dealing with some of it, and I’m not saying that some of that debris doesn’t stimulate the microspasm, but if the arteriolar bed is predilated, you can’t get away with releasing it. How often does a macroembolic piece of debris actually close off a side branch after a vein graft intervention? Probably in only one of one-hundred cases — and the filters will help with that possible incident. Thus, I’m saying that you could perform 100 procedures and save $140,000 in filter costs and about 100 hours of interventional time as well, whereas nicardipine costs about $20, as opposed to $1,400 for a filter device. Howard Cohen: Don’t you think that it works for discreet disease in vein grafts? For the diffusely diseased vein graft that is loaded with atheromatous material and clot, it’s hard to believe that simple vasodilatation will be sufficient. An incredible amount of debris is retrieved in the filters. Tim Fischell: I could show you a couple of cases we performed utilizing the AngioJet device with nicardipine and adenosine in the flush solution in vein grafts that were completely filled with clot. One case shows a perfect myocardial blush score upon completion; TIMI 3 flow was never lost. All of the clot was sucked out while delivering nicardipine and adenosine down into the microvasculature, three stents were placed (having pre-medicated with nicardipine each time) and the case was completed without a CP-K bump. This case was as bad as any you’ve ever seen — quite a bit worse, in fact, than the one Richard showed here. Thus, even a case as bad as that could theoretically be performed without distal protection. The problem with distal protection in such cases is that there is so much debris. Are you going to put the device down there six times to retrieve it all? And the same goes for the balloon: Do you ever get crevices behind the balloon where debris gets caught? The worst no-reflow I’ve ever encountered in my career involved the use of a filter. We did a balloon inflation because the protocol required it. The patient had TIMI 0 flow. It was then that I decided to abandon the filter and just pre-medicate my patients from then on. We have performed approximately 60 consecutive cases with pre-medication. You will see the results in the CREST trial hopefully within the next six months. Jeffrey Werner: I have been using nicardipine a lot and I agree that it is a very potent peripheral vasodilator. But in a case where a graft is nearly or completely occluded, if it’s administered in the guide, where does it go? Pierre and I were talking just now and we think that perhaps you should wire it, put the balloon down, pull the wire, and administer the drug through the balloon distally so that most of the drug will reach the distal vessel, even if it isn’t passing antegrade. Then the stent can be placed. Now, theoretically, the drug has been delivered distally. Tim Fischell: The beauty of nicardipine is that not only is it twice as potent as verapamil and cardizem, but it lasts twice as long as well (six minutes). So your approach could be very effective — I haven’t tried that. We have also put the drug in the flush solution of the AngioJet. Better yet, perhaps, would be to put the balloon down, inject 200 mcg distally, vasodilate, then put the AngioJet down with nicardipine to clean it out. There are thus all kinds of variations on the theme. Some physicians have tried adenosine, however it lasts only 15 seconds, so there isn’t time to do all the things I just described. A paper was published showing that adenosine really does reverse no-reflow, but because of its brief duration, you cannot pre-medicate with it, place the stent, and expect to have any protection. Howard Cohen: Adenosine, however, has other effects besides vasodilation that may be important. Tim Fischell: Yes, that’s true. Barry George: I’ve done a lot of vein graft procedures in a number of different ways. Once a no-reflow or slow-reflow phenomenon occurs, you are kicking yourself because perhaps you didn’t do something you think might have been beneficial. I agree with Tim to some extent that most of this is a vasospastic microcirculatory phenomenon due to very small particulate. Some of the work Donald Baim did was quite fascinating in that it showed that there clearly is a mechanical component to this microcirculatory obstruction as well. One of the things I learned in my early days doing carotid work was what we call the "minimal touch" technique. With that in mind, I think that whatever you can use very proficiently – that your technologists can set up without error — is well worth it! Obviously, it’s best to get the device down without mucking around so much that debris is knocked loose in the process. I think adenosine is a waste of time because of its short duration. We use self-expanding nitinol stents, particularly in cases involving long, diffuse disease — whether it’s the Radius stent, the Precise stent, etc. We oversize the stent in order to have a tightly meshed network of the nitinol. For whatever reason, nitinol does not seem to restenose as much in vein grafts as the stainless steel self-expanding stents do. Look fluoroscopically after placing the stent, and you will be pleasantly surprised the majority of the time, because it will almost always be fully expanded, with no "dog bone" where the lesion was located. And guess why: There’s just a bunch of toothpaste there. At that point, I stop, aspirate and finish up. I think this approach will really reduce the problems encountered with long, diffuse lesions. Self-expanding balloon stenting is just like squeezing toothpaste from a tube on the toe of the stent. How often have you thought: “I just don’t like it.” So you bump it a little higher until you reach 18 atms, and then slow flow occurs. It’s got to be due to the extrusion-type phenomenon. More discouraging is when the whole thing wasn’t covered and the patient returns six to eight months later with a new lesion above where the nitinol stent was placed. Thus, we are only beginning to scratch the surface of the problem with these conduits. Patricia Thorpe: In 1993 we conducted studies that show touching the vessel wall upstream releases endothelin-1 and endothelin-2. These are strong vasodilators, which may suggest how some patients are very sensitive to endothelin and develop cardiac ischemia when the aorta is cross-clamped. The peripheral vascular specialists always used nifedipine before even entering the renal arteries because there is so much subsequent vasoconstriction. We also know that when the periphery is acutely ischemic, and it’s opened up nicely with thrombolytic agents, there may be very little arteriolar runoff. We found that aside from the vasodilator concept, we could perfuse the leg with a low-dose overnight urokinase (100,000 U/hour, or now t-PA 1 mg/hour), mixed in a volume that slowly perfuses the limb. We have observed a very low incidence of reperfusion syndrome. And the next day, the vascular bed has a significant increase in“no-name” vessels that visualize by contrast by simply giving the leg a chance to: 1) reduce vasospasm; and 2) to treat the amount of in situ thrombosis that occurs with vasospasm. I understand of course that the organs are different, but I just don’t understand why interventionists wants to do things so quickly. If thrombolytics are used on some of these coronary lesions to debulk them a little with an acute amount of t-PA or urokinase, there will be less debris going downstream anyway. Afterall, vasospasm occurs when the guiding catheter is inserted. Manipulation certainly doesn’t help, but the instant that endothelium is touched, vasoconstrictive agents are released. Philip Reid: I want to return to the dramatic case that was presented involving dissipation post-op. The patient had probably been off aspirin for five days, the wound was bleeding, and a hematoma had formed. In such cases, the physician is asked to administer heparin, possibly a GP IIb/IIIa receptor blocker. On the other hand, when dealing with acute myocardial infarction patients no-reflow often does not occur — thus, patients differ. I think that case represents a classic example of post-op hypercoagulability. Extensive focus has been placed on platelets and great inroads have been made, but should we start thinking more about developing a quick test that could be performed in the E.R. to determine a patient’s hypercoagulation status? Is it very high, or low, or intermediate? Is there some protein deficiency? This would allow the physician to tailor the pharmacological treatment to the patient. Does hypercoagulability influence the no-reflow phenomenon in some patients? I don’t have the answer at this time, but it’s an issue that needs to be studied. Fayaz Shawl: The question arises on how to approach vein grafts that are 10 to 20 years old with complex thrombus-containing lesions In some cases, we put the patient on coumadin for a couple of weeks, and the results are amazing! Thirty to40% of these grafts do show marked improvement in the lesion complexity. At the last TCT meeting, a few presenters showed similar examples of improvement with coumadin/IV Lovenox. Richard, for the case you presented — unless the patient was really experiencing chest pain — I would not perform an intervention initially, but instead would put the patient on medical therapy, stabilizing the graft prior to intervention. Richard Heuser: The patient had unstable angina. I could not sit on it. Fayaz Shawl: In that case, you had no other choice, but if the patient is asymptomatic and comfortable — especially with old, long vein graft lesions — I think that it’s better not to do an intervention that could make him worse.