Stent wars

Once hailed as a surgical saviour, Healthcare Middle East asks is the tide turning against drug-eluting stents?

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By  Joanne Bladd Published  October 11, 2006

Stent wars|~|stent2.jpg|~|“Several studies have linked DES to an increased risk of myocardial infarction or death when compared to bare-metal stents, leading cardiologists to question the benefits of their widespread use.”|~|When the first drug-eluting stent (DES) earned FDA approval in 2003, it was saluted as a revolution in the field of angioplasty. Less than two months later, the FDA issued a warning to physicians to be vigilant in reporting adverse reactions in the use of the Cypher sirolimus-eluting stent following a series of thrombotic events, including five deaths. This warning sparked a heated debate over the use of drug-eluting stents, one that reached fever pitch last month at the World Congress of Cardiology meeting in Barcelona. Delegates heard from a trio of European studies that each raised concerns over the safety of DES. One, the Camenzind meta-analysis, found the incident of death or myocardial infarction increased by 2.4% in patients who received sirolimus-eluting stents, compared to patients treated with bare-metal stents. A second study, headed up by the ThoraxCenter in Rotterdam, tracked stent thrombosis rates over three years in more than 8,000-plus patients. The study reported that the cumulative rate of thrombosis in DES patients was 2.9%, but that the rate was linear, starting at 1.2% at 30 days (similar to bare metal stents) and then rising by 0.6% each year thereafter. According to these results, thrombosis risk with DES does not wane with time but continues increasing. Interestingly, these results contrast with another trial, first reported at the American College of Cardiology meeting in March this year. The Basket (Basel Stent Cost Effectiveness Trial) study found that at 18 months the rate of death or myocardial infarction was 8.4% for DES patients and 7.5% for patients treated with bare-metal stents, but that the difference was not statistically significant. Confused? So are physicians worldwide. And while the FDA has stepped in and announced plans to review the new data, it is widely acknowledged that longer, larger trials are needed to provide full answers to safety concerns. But until those answers are available, what impact do these findings have on potential and current DES patients?||**||Stent evolution|~|stent2.jpg|~|“A study published in the Journal of the American Medical Association, found that early discontinuation of dual therapy was the most important predictor of stent thrombosis, associated with a 90-fold increase in risk.”|~|This question is the latest to arise from the evolution of minimally invasive ways to tackle atherosclerosis. The process began in the 1970s, with the advent of angioplasty balloons. Although these balloons were initially widely successful in dilating blocked arteries, in a small percentage of patients abrupt artery closure would occur once the balloon was deflated. And for a larger group of patients, in up to 30% of cases, restenosis would occur, requiring the patient to undergo a second procedure. During the 1980s, an array of devices were proposed to counter these problems, and one such device was the bare-metal stent. The device could be inserted into the artery on a balloon and then ‘locked’ into place, rather like scaffolding, to ensure the artery remained open. With the advent of stents, abrupt artery closure was virtually eliminated. However, in approximately 25% of implant cases, restenosis persisted (typically at between three to six months), requiring a repeat procedure. Over time, it became clear that restenosis in these cases was a response to the ‘injury’ of angioplasty; an over-proliferation of the endothelial cells during healing. Interventional cardiologists began looking at pharmacologic solutions to the problem, prompting the development of drug-eluding stents. These stents are coated with drugs known to interfere with the inflammatory response, delaying the growth of endothelial cells and preventing restenosis. To date, two such stents have won FDA and European approval; the Cypher sirolimus-eluting stent and the Taxus paclitaxel-eluting stent. A third DES, Medtronic’s Endeavor, which uses ABT-578, received EU approval in April 2005. Initial clinical trials of drug-coated stents were promising, showed restenosis rates of approximately 5%, a marked difference from the 30% or more seen with bare-metal stents. But real life, of course, is bigger, messier, and more complicated than clinical trials. While DES solved the problems associated with their bare-metal precursors, their wide use (to date an estimated six million implants worldwide) has flagged up another issue; late stent thrombosis.||**||The backlash|~||~||~|It has long been established that bare stent surfaces are thrombogenic. The foreign metal object attracts platelets, which tend to congregate and clot, forming a thrombus. This can suddenly close off a major coronary artery, causing a myocardial infarction that could be fatal. In response, dual antiplatelet therapy, namely aspirin combined with ticlopidine (Ticlid) and more recently clopidogrel (Plavix), was routinely prescribed post-stent. This dual therapy, continued for four to six weeks, prevented clotting while endothelial cells covered the stent, eliminating the threat of thrombus. But drug-eluting stents work specifically by inhibiting or slowing cell growth, to avoid restenosis. It is thought that in some individuals, drug-eluting stents suppress cell growth too much, leading to a failure of the stent to re-endothelialise and a risk of thrombosis. Certainly, although late stent thrombosis is by no means common, several studies have linked DES to an increased risk of myocardial infarction or death when compared to bare-metal stents, leading cardiologists to question the benefits of their widespread use. Dr Ron Waksman, an interventional cardiologist at Washington Hospital Center, is one such physician. “I believe that drug-eluting stents are more thrombogenic than bare metal stents,” he says. “I feel that there is some concern not only for me, but for others in reconsidering twice why they should place a drug-eluting stent if they can still do it with a bare metal stent. “I’ve always said that 80% of the people getting drug-eluting stents don’t need them. Because they’ll never restenose. It was only 20% that restenosed.” US pathologist Dr Renu Virmani, speaking at the EuroPCR interventional cardiology meeting in Paris earlier this year, also sounded a note of warning about widespread use. “It (DES) is not for everybody There’s no need. You don’t die from a bare metal stent.” But for patients that, or potentially will, have undergone a DES implantation, it should be noted that several factors appear to influence late stent thrombosis. These include stents that don’t accurately fit an artery (correct stent sizing is crucial in proper stent placement, and variation from the optimum can sometimes give rise to complications); hypersensitivity or an allergic reaction to the stent coating, and premature discontinuation of antiplatelet therapy. ||**||Medication concerns|~|stentUPDATE.jpg|~|“If patients stopped the regimen short of a year, they should be restarted until they have accumulated 12 months,” says Dr Elliot Antman|~|Of these factors, the last seems to be the most important. A European study, published in 2005 in the Journal of the American Medical Association, found that early discontinuation of dual therapy (aspirin and clopidogrel (Plavix)) was the most important predictor of stent thrombosis, associated with a 90-fold increase in risk. Similarly, a small, early study from Harvard’s Beth Israel Deaconess Medical Center, reported that patients who stopped dual therapy too soon post-stent were 30 times more likely to develop in-stent thrombosis than those who kept taking the combination. Current American College of Cardiology/American Heart Association guidelines recommend a minimum of three months of Plavix plus aspirin for patients who receive Cypher stents, and six months of dual therapy for those who have Taxus stents implanted. Patients who have no excess bleeding risk should take both drugs for a year. According to Dr Andrew Eisenhauer, who directs the Interventional Cardiovascular Medicine Service at Harvard-affiliated Brigham and Women’s Hospital, these guidelines should be considered the bare minimum. Dr Elliot Antman, a professor of medicine at Harvard Medical School, goes one step further, advising physicians to ensure that patients have completed a year of dual antiplatelet therapy. “If patients stopped the regimen short of a year, they should be restarted until they have accumulated 12 months,” he says. However, dual therapy raises its own concerns. Many cardiologists prescribe Plavix for a year and aspirin for life. Outside of the expense (Plavix can cost up to US $4 per day), this therapy is not without side effects. A number of patients are allergic to Plavix, some quite substantially. Add to this the fact that these blood-thinning medications are not welcome if the patient requires surgery, and it is no surprise that patient compliance with antiplatelet therapy is often less than optimal. Patients are often instructed to stop taking aspirin and Plavix a few days before an operation, often by a primary care physician, with sometimes unintended and dire consequences. Surgery isn’t the only hurdle. Should a patient suffer from any condition that makes it impossible to keep food or medications down for a few days, the chances of stent thrombosis increase.||**||Advising patients|~|stentUPDATE.jpg|~|For primary care physicians, advising patients on whether to opt for drug-eluting stents or their bare-metal counterparts is a difficult task. |~|For primary care physicians, advising patients on whether to opt for drug-eluting stents or their bare-metal counterparts is a difficult task. Patients facing this prospect should “have a very frank discussion with their cardiologist about the risks and benefits of each kind of stent,” says Dr Aloke Finn, a cardiologist at Harvard-affiliated Massachusetts General Hospital. He and others at Mass General are among a small but growing number of doctors who think that preventing the aggravation of restenosis from a bare-metal stent isn’t worth the small but real risk of having myocardial infarction with a drug-eluting stent. During the discussion, the cardiologist should be informed of other potential health issues that may require surgery in the future that might prevent the continuation of antiplatelet therapy. It is essential to note, and ensure the patient is aware, that dual therapy should only be discontinued after consultation with the cardiologist. As Antman stresses, “I tell patients don’t stop any drug without talking to me.” Equally, if a patient presents with any condition that prevents him/her taking antiplatelet therapy for more than two days, “that’s a medical emergency,” says Eisenhauer. Again, the cardiologist should be informed. ||**||The future for DES|~||~||~|The problems stated above are not new and a number of companies have been developing innovative technologies that avoid some of the problems with current DES (see ‘At a glance’). It is hoped that one of these second generation devices will prevent both restenosis and late blood clots, but whether they generate new problems of their own remains to be seen. With the advent of new devices, and a drive towards more careful patient selection singling out who will benefit most from the use of drug-eluting stents, the trends in treatment for coronary artery disease may well see a significant change in the near future. ||**||At a glance: DES, the next generation|~||~||~|- New coats The current generation of drug-coated stents are just bare-metal stents covered with a polymer coating that holds and releases a drug that inhibits the growth of endothelial cells. It’s possible that the polymers being used, or cracks in them, may be responsible for the formation of blood clots. Several companies are working on polymers that are more compatible with the body and less likely to trigger clots. Others are testing polymers that dissolve and disappear after a while. - New drugs Several next-generation stents replace sirolimus or paclitaxel with drugs that aren’t quite as aggressive against, or toxic to, endothelial cells. These include several ‘limus’ drugs: biolimus, everolimus, tacrolimus, and zotarolimus. At the World Congress of Cardiology meeting in Barcelona, an investigational DES called Xience, which is coated with everolimus, was reported to significantly outperform Taxus in early trials. - Double action Another interesting approach involves latching a cell-inhibiting drug onto the outside of the stent, which comes into contact with the artery wall, and coating the inside with an agent that prevents blood clots. - Call in the cavalry A stent coated with a substance that attracts immature, endothelial-like cells from the bloodstream may help ease the overgrowth of cells that are injured when the stent is expanded inside an artery. - Go naked Bare-metal stents could also make a comeback if a sirolimus pill pans out. The results of a small trial, published in the 18 April 2006 edition of Circulation, show that taking sirolimus every day for just two weeks after having a bare-metal stent implanted works almost as well as receiving a sirolimus-releasing stent. However, side effects, especially sores in the mouth, could be a major hurdle to this approach. * Parts of this article have been adapted from information supplied by the independent educational health site, which provides breaking news and current content on the field of stents and angioplasty.||**||

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