The circumspection stems from a nagging uncertainty over the real-world risk of stent thrombosis in DES and the prickling premonitions that a late catch-up phenomenon may still erode the impressive mid- to long-term results. And while experts interviewed by heartwire spoke glowingly of the next-generation stents, there is the widespread acknowledgement that the two most commonly used devices, the Cypher and Taxus, while still the best option in many patients, likely have shortcomings that can be overcome only by tweaking the drug and delivery mechanisms.

"There is some sense that people are perhaps more worried than they were before about stent thrombosis and other safety issues," Dr Campbell Rogers (Brigham and Women's Hospital, Boston, MA) told heartwire. "I have the feeling that people may be pulling back a lot more here, in Europe, than in the US, but it still strikes me that it's probably a minor effect, and DES remain the standard interventional treatment for coronary disease. There really hasn't been any deviation from that."

Yet, perhaps even more than ever before, EuroPCR attendees turned out in droves to see Dr Renu Virmani's annual cautionary tales. Of note, Virmani (CV Path, Gaithersburg, MD), long considered the leading DES spoilsport, was this year's recipient of the EuroPCR's Ethica award, which honors an individual's contribution to the field of interventional cardiology—a telling indication that interventionalists may be starting to tune in to her words of warning.

If you asked me, I'd take the restenosis.

In back-to-back sessions Thursday, Virmani reminded her audience about the BASKET-LATE results—reported by heartwire from the American College of Cardiology 2006 meeting. In this trial, one year after clopidogrel was stopped, restenosis-related target vessel revascularizations (TVRs) were no longer significantly different in DES- vs bare-metal-stent-treated patients, while cardiac death and nonfatal MI were higher in patients who received DES. While not explicitly powered to detect differences in late stent thrombosis, the BASKET-LATE results suggested that among 100 people treated, three would die or have an MI for every three cases of restenosis prevented, Virmani stressed.

"If you asked me, I'd take the restenosis," she quipped.

Dr Renu Virmani

Much of Virmani's message takes the form of autopsy cases illustrating the pathologic mechanisms of stent thrombosis. Time and again, Virmani showed stent cross-sections with evidence of thrombi, hypersensitivity reactions (likely to the drug or polymer), nonendothelialized stents, and no evidence of smooth-muscle or endothelial cells essential to the healing process six months or more after stent implantation. In one case presented by Virmani, a 65-year-old man who died from a traumatic brain injury had one Cypher and one bare BX Velocity stent implanted 15 months previously. Sections of both stents dramatically illustrated the differences in neointima formation, endothelialization, and inflammatory response.

Moving on to animal data, Virmani showed study results comparing endothelialization in bare-metal stents with that of DES out to 40 months. Within three months, endothelialization was significantly better for the bare-metal stents than the DES, reaching 80% to 90% reendothelialization by 40 months. By contrast, endothelialization for the DES never exceeded 50%. Without a doubt, Virmani cautioned, "We have a problem with poor endothelialization in DES."

In equally galvanizing data, shown during a Medtronic-sponsored session, Virmani showed scanning-electron-microscope images comparing Medtronic's bare-metal Driver stent with an everolimus-eluting Endeavor, Cypher, and Taxus stent, all of which included overlapping stent sections. Strikingly, while there were no apparent differences in strut-surface coverage between the Endeavor and the Driver (which is the Endeavor's stent platform), both the Cypher and Taxus showed significantly less endothelialization and stent strut coverage, a finding confirmed using computerized morphometrics, Virmani said.

These observations should prompt a rethinking of late loss, she argued. In recent years, late loss has been held up as the be-all and end-all of surrogate end points in DES research. Indeed, the Endeavor stent, available in Europe but not in North America, has at times been criticized for its higher late-loss results alongside the Cypher and Taxus.

But as Virmani sees it, late loss may have been unfairly demonized: "Late loss is not the solution for long-term success—instead, the amount of uncovered stent is directly related to thrombus," she argued. "I think we need to reconsider the idea that late loss is the answer to restenosis. . . . Neointimal formation is not all bad—a little will go a long way, as it promotes endothelialization."

Summing up her autopsy and animal-study findings, Virmani singled out the primary causes of stent thrombosis as: stoppage of dual antiplatelet therapy; polymers, which induce inflammation and may lead to late stent thrombosis secondary to hypersensitivity reactions; reduced smooth-muscle-cell presence and delayed endothelialization caused by cytotoxic/cytostatic drugs; stent bifurcation; stent malapposition; and finally, increased stent length, which increases the likelihood of inadequate stent strut coverage.

"DES late stent thrombosis is a great safety concern," she concluded. "We need to be prudent when we're using DES. . . . Vessels greater than 2.8 mm should not receive DES."

In an interview with heartwire, Virmani said she believes interventionalists are finally starting to listen to her oft-expressed concerns, and those who aren't "must have blinders on."

"I think people are coming around and learning that there is a problem with DES and that we need to improve the safety." In the meantime, she added, "I think that people should be holding back on their use of DES, absolutely, especially in larger vessels and nondiabetics. There is no indication for DES in large vessels."

Throughout the EuroPCR meeting, presenters and moderators alike revisited the question of when a bare-metal stent might be the better option. In a session dedicated to the challenges of dual antiplatelet discontinuation, Dr Jean Marco (Clinique Pasteur, Toulouse, France) highlighted the complex settings in which a DES may not be the best choice, given the established risks of stopping clopidogrel. Often overlooked, he noted, is the fact that men over 60 are increasingly at risk for prostate cancer, which may be diagnosed only after DES implantation, leaving physicians with a major dilemma: stopping clopidogrel or postponing surgery. In elderly patients, he added, the risk of a fall requiring orthopedic surgery is a major consideration.

Before you decide whether to use a drug-eluting or bare-metal stent, you have to be sure that in the next three [to] 12 months, the patients will not stop or need to stop dual antiplatelet therapy for any reason.

Given these potential risks, he said, "The interventional cardiologist is legally bound to provide clear information to the patient and the patient's family on the potential problems of stopping clopidogrel before implantation of DES."

Marco's rule of thumb is as follows, he said: "For nondiabetic patients with short lesions and vessels larger than 3.5 mm, I believe that use of bare-metal stents is a good choice. And the second part of the equation is that, before you decide whether to use a drug-eluting or bare-metal stent, you have to be sure that in the next three, four, or 12 months, the patients will not stop or need to stop dual antiplatelet therapy for any reason. If the answer is, I don't know, then I believe that the bare-metal stent is better."

Elsewhere during the EuroPCR, Dr Giuseppe Sangiorgi (San Raffaele Hospital, Milan, Italy) borrowed a joke from a recent editorial by Colombo and Corbett highlighting the delicacy of the situation [1]. As the joke goes, a patient asks his doctor how long he has to stay on clopidogrel following DES, to which the doctor replies: "For one year, or, better still, until you find a physician who tells you that you can stop."

But the clopidogrel problem, says Dr Aloke V Finn (Massachusetts General Hospital, Boston), is no laughing matter. He pointed to the recent CHARISMA trial, which showed no benefit—and potential harm—of long-term clopidogrel plus aspirin in stable CAD patients.

"You can't continue people on Plavix forever, it's not a benign drug," Finn told heartwire. The only alternative, he says, is: "Don't use as many DES: for vessel sizes greater than 3.0 mm, I don't routinely use a DES. In fact, I almost never use a DES unless I'm absolutely sure that the patient can take long-term Plavix, and that would always be a younger patient."

Finn admits he has his biases: for one, he is Virmani's son. But beyond filial respect, he says he has had an opportunity that many interventional cardiologists do not: to see first-hand the pathological changes following DES implantation. "If you're an interventional cardiologist, you haven't seen the human pathology, you haven't done all the animal models, and those are very important."

For example, he says, "For the Taxus stent program, the animal studies were never published, so they've never been available for people to understand the long-term effects. You'd have to do your own special investigation, which no interventional cardiologist is going to do. So until you see clinical data that really convince you, you don't worry about it, but I think it's becoming more and more obvious that there is a worrisome effect of DES."

Moving forward

In an interview with heartwire, Dr Patrick Serruys (Erasmus University Hospital, Rotterdam, the Netherlands) acknowledged that the clopidogrel dilemma is "a big issue," but he stopped short of saying that the bloom had gone off DES use altogether.

"First, you have to know whether you are dealing with an individual who is more or less resistant to aspirin or clopidogrel, and this can be tested. . . . For the time being, my advice is to keep the patient on aspirin, and if you have very intensive use of these stents, prolong clopidogrel to one year."

Any time there is a new problem, the new problem needs to be resolved, but that's happening, and the world keeps moving so fast.

Serruys believes the dual antiplatelet problem will be resolved by next-generation stents that will do away with the excessive cytostatic and cytotoxic effects of drugs like sirolimus and paclitaxel. As well, dual-elution devices, combining heparin and sirolimus combinations or zotarolimus and dexamethasone, for example, will effectively solve the antiproliferative and antithrombotic effects in the setting of a single stent.

"Any time there is a new problem, the new problem needs to be resolved, but that's happening, and the world keeps moving so fast," he said philosophically. "I think it's time to go to the second-generation stents."

And despite what appears to be a greater willingness to hear Virmani's concerns, the foremost experts in the field insist a return to bare-metal stents is not the answer. "I think Renu is right, we have concern, the stent-thrombosis problem is there, but it is relatively overemphasized," Dr Antonio Colombo (EMO Centro Cuore Columbus, Milan, Italy) commented. But he, for one, is not going to hold back on DES implantation in appropriate patients.

"We implant millions of DES and people are not dropping dead one after the other," Colombo said. "So we know there is a problem and we need a new generation of drug-eluting stents, but we should not move back to bare-metal stents, we should move forward toward a better DES."