Stent Thrombosis: A Wake-Up Call?

The current definition of stent thrombosis, as put forward by Dr. Donald Cutlip and the Academic Research Consortium at the October 2006 TCT meeting, places subacute thrombosis occurring in the first 30 days, late thrombosis occurring after one month and very late thrombosis occurring after 12 months. There is very little data on predictors of late or very late stent thrombosis. Certain subgroups, such as patients with renal failure, diabetes and those with low ejection fractions seem to track with late stent thrombosis. Lesion morphology, such as bifurcations, very long lesions and thrombus-containing lesions, also appear to be at higher risk. By far, the most important predictor of stent thrombosis (at any time) is discontinuation of dual antiplatet therapy (aspirin and a thienopyridine). Drug-eluting stent (DES) late thrombosis is a relatively new topic. Most of what we know was done with bare metal stents and is from older literature, yet there’s no reason to believe the subacute thrombosis data would be different using drug-eluting stents. What is different now with DES is that thrombosis is occurring so late, and, in some cases, many months after stopping dual anti-platelet therapy. We have learned some important lesions related to implantation techniques over the past 13 years since stents were approved. Probably the most important thing we have learned from intravascular ultrasound (IVUS) is that inadequate stent expansion is a major contributor for both restenosis and stent thrombosis. We have never looked at stent thrombosis in prospective studies, because the frequency has been so low. Much of the data today are from retrospective reviews of patients who did have a thrombosis, and there is no clear prospective study that links any IVUS finding to stent thrombosis. That data just does not exist. This is quite different from restenosis, where we have many predictors clearly identified. Yet we do know that most of the people with stent thrombosis have some abnormalities as seen on IVUS and that their stents are often underexpanded. In the POST trial, which looked at acute and subacute thrombosis in bare metal stents, IVUS showed abnormalities in 95% of stent thrombosis cases; the bulk of these were stent underexpansion, although there were also a small number of uncovered dissections. Angiography only identified abnormalities in 32% of cases.¹ We have also been able to determine that inadequate stent expansion, by which I mean an in-stent minimal lumen area less than 80% of the adjacent reference segment lumen area, is associated with a higher rate of restenosis and target lesion revascularization. Restenosis with DES is similar; typically at the site where the stent is not well-expanded. It is very clear that using angiographic guidance alone is inadequate in order to determine whether you have chosen a proper size stent, whether you fully have covered the area that you intended and whether you have achieved adequate expansion. There are a host of studies that go with each of those points, but probably one of the more interesting ones is the STLLR trial, just presented at TCT 06 by Dr. Marco Costa. STLLR showed that almost two-thirds of patients who received a DES had geographic miss. That means the stents were either the wrong size in diameter or they didn’t completely cover the lesion area that had been predilated. These patients had a worse outcome than the ones who did not have geographic miss. So, even in the DES era, it looks like angiographic guidance is not completely accurate in determining where to put these stents and what size to use. Why does IVUS remain only a recommended part of a stenting procedure rather than a required part of the protocol? This issue continues to bother me as well. I’ve been doing IVUS since 1987 and actually did the first human coronary IVUS in the United States. I’ve done over 100 training courses since then. It has been frustrating to have an IVUS use penetration level of only 8-9% in this country. There are all kinds of reasons why people don’t use IVUS, and most of them have nothing to do with the science. Almost any of the interventionalists you talk to understand the benefits of IVUS, but there hasn’t been a great incentive for them to use it because nobody is challenging them. They can get by with the procedure, the patients do okay acutely and nobody’s coming back in 6 months saying, Hey, why didn’t you do IVUS on my lesion? Maybe I wouldn’t have had restenosis. There has been no external pressure, although I think that is now going to change. Since the data were presented regarding late stent thrombosis, Boston Scientific and Volcano Corporation have both seen the use of IVUS increase quite significantly. It was a wake-up call for people that were being a little bit cavalier, honestly, in their stent implantation technique. Hopefully, more interventionalists will now go on to use IVUS to ensure optimal stent implantation. In Japan, IVUS usage is in the range of 65-70%. The U.S., as an interventional community, has frankly been slow to catch on. I should note that the cath lab staff are very important to a successful IVUS program. At least half to two-thirds of the people I train are technologists and nurses. Most labs have their techs and nurses operating the machine. The physician moves the catheter and the techs and nurses operate the machine, not unlike what they do in the cath lab with hemodynamic monitoring. We focus on training the techs and nurses how to do IVUS and how to get the right quantitative information. Measurement of lumen diameters to select stent size and lumen areas to optimize expansion are the key take-home points. What has been done to improve the IVUS technology from a user standpoint? IVUS has now been incorporated into the cath labs at the bedside. Both Volcano and Boston Scientific have integrated systems which allow immediate IVUS access in all of the cath labs. Newer systems also have automated border detection which allows more rapid determination of the key measurements needed to guide intervention. We hope that this ease of use will bring more people back to what they already know and understand about the importance of proper stent implantation. Should IVUS be used both pre- and post-stent placement? What we’re recommending is at the very least you use it post-stent placement, to determine whether the stent is well-deployed, well-expanded, and covering all of the lesion it should cover. Those of us who use this technology on a routine basis, however, would uniformly suggest the use of IVUS pre-procedure. By imaging pre-procedure, you can tell what size stent to use, measure the length of the stent to use and thus start out with the right device. You can also assess the plaque, looking in particular for calcium. When there’s a lot of calcium, it markedly impairs your ability to expand the stents. We’ve got case after case example of stents that were put in under angiographic guidance and then could not be fully expanded. These patients went on to have problems with thrombosis or restenosis. Once you’ve implanted a stent into a ring of calcium, at times it is often impossible to open the stent. We would advocate making sure that you don’t have a lot of calcium beforehand, or if you do, to pretreat it and modify that calcium. Pretreatment could include rotational atherectomy, a cutting balloon, or just a regular predilatation balloon to try and first crack the calcium before you put the stent in on top of it. How do you utilize IVUS in your own practice? In my practice, we use IVUS 68% of the time. There are certainly some cases, usually short lesions in big vessels in younger patients, where we don’t routinely use it. The other time where we don’t routinely use IVUS is in very small vessels where there are really not a lot of other options. If it’s a 2.0 or 2.25 mm vessel, there are not many other choices. Still, the majority of cases can benefit from the use of IVUS, and in my mind, the more complex the case, the more high-risk the case, the more we need IVUS. Bifurcations, ostials, left mains, relatively small vessels in diabetics, long lesions all the things that we know have a higher restenosis rate these patients are going to benefit the most, and these types of cases make up a high percentage of what we do today. The other place I would never go without IVUS is chronic stable angina in older people because these patients almost always have a lot of calcium. In addition, I certainly use IVUS in any patient where I have concerns about exactly what the lesion looks like. Perhaps the lesion is unclear on the angiogram, it is near branches or I’ve got questions about whether it involves the ostial left main or a major diagonal ostium. I have to struggle to find a patient where I don’t want to use IVUS. What about the use of fractional flow reserve (FFR) along with IVUS? We do a lot of FFR. FFR is by far and away the preferred diagnostic tool for assessing lesion severity. It’s different than IVUS. IVUS looks at anatomy: plaque composition, vessel diameter, etc., and gives you a lot of information about how to proceed with an intervention, and then, if that intervention has been satisfactory. FFR, on the other hand, is best utilized for assessing whether a lesion is flow-limiting and actually needs to be intervened upon at all. It’s really a diagnostic test. If we have a patient with a lesion that isn’t obviously in need of therapy, then we will use FFR to determine whether that lesion is limiting flow or not. We would only do intervention if it was shown to be abnormal. We don’t do coronary flow reserve (CFR) for lesion assessment any more. There are a number of reasons for that, but mainly, it’s just not specific enough for the lesion. Could you summarize the challenges you see now for IVUS? Marketing surveys show physicians mentioned three big things as reasons why they don’t want to do IVUS. First, it takes too much time and/or costs too much money. In fact, we have several studies that show it adds only about 5 minutes to the procedure. Studies also show IVUS actually provides a cost savings. Since restenosis and acute problems are reduced, you actually save money by doing IVUS with all patients. This data is from the Strategy for Intravascular ultrasound (IVUS) guided PTCA and Stenting (SIPS) trial, back the late 1990s. I have a hard time if a physician tells me they can’t waste another five minutes doing IVUS to lessen their patient’s chance of restenosis by 30-40%. I find that difficult to justify. IVUS does not take a long time, it’s not very expensive and it is well reimbursed. It doesn’t take a drastic reduction in adverse events for IVUS to pay for itself very quickly. Additionally, fewer extra stents from underestimating lesion length, enhanced bare metal stent use and fewer misadventures certainly helps the cath lab budget. The second complaint was that there wasn’t any clinical data. That’s just false. There are nine angiographic versus IVUS-guided stent studies. Eight are in favor of IVUS and one was neutral. There is plenty of data that IVUS-guided expandable stent implantation gives you a better outcome, both acutely and chronically. Finally, physicians said they couldn’t interpret the images, they didn’t know how to work the machine and it was too technically challenging for them. Today, IVUS has really come a long way in terms of user-friendliness. To do an intervention, lumen diameters and lumen areas are really all you need, and these are very simple to do now. For plaque composition, the images are now color-coded, and so with a minor amount of training, anyone can do IVUS, interpret it and analyze the findings. It’s my belief that we have tackled all three of these major limitations and any lingering disinterest in IVUS is really more of a mental block on the part of the interventional physician. I hate to be cynical but there’s a lot of folks out there doing an intervention who just want to get in, get out and get onto the next thing. I’m hoping that the DES thrombosis issues will wake people up to the responsibility we all have, to do as good a job technically as possible. I think the data with IVUS is really remarkable and consistent. It would be very hard for me to justify having not used IVUS if questioned later about why a patient had a bad outcome. Late thrombosis with DES is a wake-up call for everyone. We need to get back to basics and be sure that we are first, stenting lesions that really need to be stented. That’s where FFR can be helpful if you don’t already have a stress test. Second, we need to make sure that when we do decide to do a stent, that we are careful to choose the right kind of stent, based on the lesion and patient characteristics, including concerns about whether they can or can’t take clopidogrel long-term. Finally, once we decide whether it’s going to be a bare metal stent or DES, we must do everything we can, particularly using IVUS, to be sure that we have appropriately and adequately implanted that stent. We all have that obligation to our patients. Dr. Hodgson can be contacted at John.Hodgson@chw.edu John McB. Hodgson’s field of specialization is invasive and interventional cardiology, particularly intravascular ultrasound, a technology he helped develop. He is Past President of the Society for Cardiovascular Angiography and Interventions. Dr. Hodgson has several patents and has also produced award-winning web-based image interpretation tools for health care professionals. Dr. Hodgson has served as an editorial consultant to many journals and has authored or co-authored over 200 articles, book chapters and interactive teaching tools. Dr. Hodgson chairs the SCAI DES Task force and most recently was the lead author for the SCAI Clinical Alert issued in response to the DES thrombosis issue.

1. Uren NG, Schwarzacher SP, Metz JA, et al. Predictors and outcomes of stent thrombosis: an intravascular ultrasound registry. Eur Heart J 2002 Jan;23(2):124-132.