Making sense of stents
Physicians debate best practice in light of new findings
From the May ACP Hospitalist, copyright © 2007 by the American College of Physicians.
By Susan FitzGerald
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Sidebar: Stents make headlines at 2007 cardiology conference |
Raymond Gibbons, MD, a cardiologist at the Mayo Clinic in Rochester, Minn., had a patient who was hospitalized with severe chest pain at rest and found to have a blockage in one artery. The man's medical history showed that he had previously undergone abdominal surgery and had since experienced abdominal pain. A recent CT indicated a possible abscess.
Should the patient get a stent to relieve his cardiac symptoms? Or should he be treated with medical therapy, at least until his abdominal problem was resolved?
Dr. Gibbons decided against the stent.
"This man could need abdominal surgery in the near future for an abscess, and that is much more pressing than his single-vessel coronary disease," said Dr. Gibbons, who is president of the American Heart Association (AHA).
Ingrowth of tissue may cause bare-metal stents to become obstructed, resulting in the need for a second procedure. Drug-eluting stents inhibit this process, but uncovered struts may be prone to thrombosis after discontinuation of antiplatelet therapy. The New England Journal of Medicine© 2007.
Doctors at hospitals around the country are sorting through similar scenarios amid new concerns that patients who get drug-eluting stents are at risk for potentially deadly stent thrombosis for months and even years after the devices are implanted. A new scientific advisory—drawn up by the AHA, the American College of Cardiology (ACC) and other professional groups—emphasizes the need for patients with drug-coated stents to remain on dual antiplatelet therapy and avoid elective surgery for a year because of the risk that comes with stopping the daily regimen of aspirin and clopidogrel for an operation.
While the risk of clotting associated with drug-coated stents is small, it's a life-threatening complication. "If someone has stent thrombosis, it's not just a mild heart attack. There's a high mortality," Dr. Gibbons said.
That concern is adding new layers to medical and surgical evaluations and decision making. Should a patient with a recently implanted drug-coated stent have a hip replacement? Should a patient who will probably need a hip replacement down the road be given a stent? If surgery is unavoidable—for example, if a broken hip needs to be repaired—then what's the best way to manage the patient before, during and after the operation?
"We need to be thinking of the whole patient, not just the heart or not just the non-cardiac surgery," Dr. Gibbons said. "There needs to be more thinking and more coordinated decision making given our current state of knowledge on stents."
The story so far
About 1 million patients annually in the U.S. get stents, most often drug-eluting stents instead of the older bare-metal ones. Because clotting is most likely to happen in the first months after stents are implanted, patients used to be instructed to take aspirin and clopidogrel for three or six months, depending on which brand of drug-coated stent they got. Patients who get bare-metal stents are normally instructed to take the anti-clotting drugs for at least one month.
Concern over the possibility of delayed thrombosis began to grow in 2006 when longer-term data on drug-eluting stents were presented in March at the ACC's annual meeting and in September at the World Congress of Cardiology meeting. The data suggested a small but significant increase in the rate of death and myocardial infarction in patients followed for one and a half to three years after stent implantation, according to an FDA statement issued after the second meeting. In December 2006, an FDA panel held a two-day meeting to review the latest information, but the session did not settle the debate.
According to an FDA summary, the panel concluded that there did appear to be an increased risk of late thrombosis associated with drug-eluting stents compared with bare-metal stents, but the panel said that analyses presented by two stent manufacturers did not suggest an increased risk of death or MI. The panel said the magnitude of the late thrombosis problem is not clear, although the risk is higher with off-label use of the devices. Drug-coated stents are approved for discrete, newly diagnosed coronary lesions in clinically stable patients who have no other serious medical conditions, but they are often used in more complex cases.
The panel agreed with recommendations that patients who are at low risk of bleeding be kept on dual antiplatelet therapy for at least 12 months. To help clarify questions that are still unresolved, the panel said that future stent studies needed to be larger and longer and include stent thrombosis as an end point, according to the summary.
"Although the absolute risk appears to be less than 2% throughout the first three years after implantation when stents are used for the approved indications, thrombosis with drug-eluting stents is a clinically important problem that may occur long after implantation," FDA officials wrote in a perspective piece published in the March 8, 2007 New England Journal of Medicine. "It is uncertain whether cases of late stent thrombosis will continue to accrue with longer-term follow-up."
The scientific advisory issued by the AHA and ACC—along with the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons and the American Dental Association, with input from ACP—underscored that stent thrombosis is often a catastrophic event. "In a pooled analysis of six trials and registries from the 1990s, the incidence of death or MI associated with angiographically documented stent thrombosis was found to be 64.4%," the advisory said. It also pointed to one large study that found that clotting occurred in 29% of patients who stopped their antiplatelet therapy prematurely.
Stents and hospital medicine
The uproar over stents may have varied effects on hospitalists' practice, especially in the area of perioperative medicine.
"The hospitalist plays the role of being a vigilant advocate for the patient," said Donald E. Casey, Jr., FACP, who represented the College on the committee of professional groups that drafted the scientific advisory on stents.
For patients with existing stents who are considering surgery, hospitalists may need to facilitate the flow of information between the cardiologist and surgeon, seeing that all needed consultations get done and that, for example, a patient's antiplatelet therapy is not inadvertently stopped without consensus. Hospitalists should also ensure that a full and detailed medical history is obtained from a patient with an existing stent, including what kind it is and when and in what location it was implanted.
Hospitalists play a key role in patient education as well.
"The hospitalist can be very influential in making sure that patients and their families understand the importance of not discontinuing their medications," said Dr. Casey, who is vice president for quality and chief medical officer for Atlantic Health in Morristown, N.J.
Andrew D. Auerbach, ACP Member, a hospitalist at the University of California, San Francisco, said questions involving drug-coated stents are coming up more and more in his work managing patients who are scheduled for surgery.
"We have this conundrum: We have a patient with a stent in place and we want to keep them on aspirin and [clopidogrel] during surgery. How do you manage that during hospitalization?" Dr. Auerbach said. "It used to be we'd say, 'If you had a stent in place more than six months, stop the aspirin and [clopidogrel] and go ahead and get your hip replaced.' But that's feeling less and less comfortable."
Stents and surgery
There is no agreed-upon protocol for how to manage surgical patients with recently implanted drug-coated stents, and practices vary from doctor to doctor and from hospital to hospital. Because patients with bare-metal stents aren't on anti-clotting drugs for long, the surgery issue doesn't come up as often.
Most cardiologists would prefer that patients with stents remain on both aspirin and clopidogrel, but that idea usually doesn't go over well with surgeons. "They're more worried about bleeding," Dr. Auerbach said. "And it's ultimately the surgeon's call."
The surgeon may be willing to keep patients on aspirin, and the goal then becomes limiting the time off clopidogrel.
Daniel M. Kolansky, FACP, an interventional cardiologist who directs the cardiac care unit at the Hospital of the University of Pennsylvania in Philadelphia, said patients who have a recent drug-coated stent (implanted less than a year ago) typically are told to stop clopidogrel five days before surgery, and, ideally, resume the medication 12 to 24 hours afterward. Dr. Kolansky said vascular surgeons tend to be more willing to accept some bleeding during surgery, and may agree to keep the clopidogrel going. But he said other surgical specialists, including orthopedic surgeons and general surgeons, also need to consider why it may be beneficial to "loosen their requirements and be more flexible" about keeping patients on anti-clotting drugs.
"We are navigating this issue … and we're learning more about it every day," he said.
According to Dr. Kolansky, in an ideal situation, the interventional cardiologist knows ahead of time that a patient may need surgery and the decision can then be made to use a bare-metal stent, which requires a short regimen of anti-clotting drugs. But many surgeries are unanticipated.
Some cardiologists opt to admit patients with recent stents before surgery to administer shorter-acting anti-clotting agents. Sanjay Kaul, MD, director of the Vascular Physiology and Thrombosis Research Laboratory at Cedars-Sinai Medical Center in Los Angeles, has his patients stop clopidogrel four to five days before surgery. He then admits them two days ahead of surgery to administer intravenous doses of a short-acting glycoprotein IIb/IIIa inhibitor as a bridge between when the clopidogrel is stopped and resumed. Dr. Kaul said this approach is based on his best clinical judgment, though the scientific advisory from the AHA and other groups said there is no evidence that "bridging" agents do any good.
Dr. Kaul said the whole issue of clotting would not loom large if doctors and patients had not been so gung ho about stents in the first place.
"The root cause of the problem is our enthusiastic use of stenting for chronic stable angina," Dr. Kaul said. "There's never been any evidence to suggest that stenting is superior to medical therapy, optimal aggressive medical therapy, in prolonging survival or reducing heart attacks."
New research raises more questions
A recent report in the New England Journal of Medicine seems to drive this point home. The COURAGE study, published in March to coincide with the ACC's annual conference in New Orleans (see sidebar and related story),[Insert links to sidebar 1 below and story 2] found that stents offered no real benefit over medical therapy for patients with stable coronary disease.
The authors examined 2,287 people with stable coronary disease and found that while patients who got angioplasty and stents (most got bare-metal stents because coated ones were not yet in use) had some initial relief from symptoms of angina, they did not have fewer heart attacks or live longer than patients treated with medication.
The study concluded that percutaneous coronary intervention "can be safely deferred in patients with stable coronary artery disease, even in those with extensive, multivessel involvement and inducible ischemia, provided that intensive, multifaceted medical therapy is instituted and maintained."
Yet another study presented at ACC '07 implied that real-world use of the CYPHER stent is safer than was shown in clinical trials. According to the MATRIX Registry, which is sponsored by Cordis, CYPHER's manufacturer, rates of stent thrombosis at one year were lower than clinical trials reported. Most patients in the MATRIX Registry, up to 80%, have chronic conditions such as diabetes that would have disqualified them from clinical trials, and therefore received stents off-label. MATRIX investigators also found that many patients had trouble maintaining the clopidogrel regimen and that one-third were no longer taking the drug as recommended at one year.
Older therapies back in fashion
There are indications that clotting worries are bringing bare-metal stents back into fashion, and even reviving interest in coronary artery bypass surgery.
Kim Eagle, FACP, chief of clinical cardiology at the University of Michigan in Ann Arbor, Mich., said that since the heightened concerns over clotting surfaced last year, the use of drug-eluting stents at his hospital has decreased from about 79% of all stenting cases to about 60%.
"We're probably moving back to a more balanced approach, taking each individual patient's profile into account," Dr. Eagle said.
Doctors are hoping the next generation of stents under development will reduce the clotting problem. The new versions include stents coated with different and perhaps better drugs, and biodegradable stents.
In the meantime, David L. Fischman, ACP Member, co-director of the cardiac catheterization laboratory at Thomas Jefferson University Hospital in Philadelphia, predicts a "back to the future" movement as doctors rediscover the virtues of bare-metal stents.
His group will present an abstract by that title at an upcoming meeting of the Society for Cardiac Angiography and Interventions. Dr. Fischman and his colleagues studied patients with bare-metal stents who received four weeks of clopidogrel and then underwent non-cardiac surgery shortly afterward. Stent thrombosis was not a problem, Dr. Fischman said.
According to Dr. Fischman, doctors need to take time to discuss with patients the pros and cons of whichever approach is being considered: bare stent, coated stent or medical management.
"It's all about communication," Dr. Fischman said. "It's about talking to the patient and getting all the information up front."
Susan FitzGerald is a freelance writer in Philadelphia.
Stents make headlines at 2007 cardiology conference
Stents were a major topic of discussion at the American College of Cardiology's 56th Annual Scientific Session in March, given the unveiling of the COURAGE findings that stents didn't improve death or cardiac event rates when added to optimal medical therapy for patients with stable coronary artery disease. While this study understandably held the limelight, others that addressed the safety of novel and existing stents caught the interest of cardiologists as well.
SPIRIT III tested the safety of a new stent that is coated with everolimus instead of the commonly used paclitaxel. At 65 U.S. sites, 1,002 patients with coronary lesions were randomly assigned in a 2-1 ratio to stent implantation with either the second-generation Xience™ V Everolimus Eluting Coronary Stent System (EES) or the Taxus® paclitaxel-eluting stent. Nine months later, rates of death, MI and stent thrombosis were similar, but EES patients saw decreased angiographic restenosis and fewer major adverse cardiac events.
ABSORB tested a new, temporary stent that works for six months, then dissolves within two years. Thirty patients, each with one coronary artery lesion, at four clinical sites in Europe and New Zealand were treated with a bioabsorbable stent made of polylactic acid and coated with everolimus. At 30 days, efficacy was 94%, ease of deployment and safety was 100%, stent recoil was 7% and no patients experienced major adverse cardiac events or stent thrombosis. At 180 days, one patient had had a mild heart attack.
ISAR-PEACE randomly assigned 500 patients to receive either a rapamycin-eluting stent or a new stent that eluted rapamycin plus estradiol, which researchers hoped might promote rapid reendothelialization. Researchers found no difference between the groups on any measure, including incidence of death, MI, stent thrombosis or binary restenosis.
DEDICATION found that combining a stent with a filterwire to catch debris and prevent it from lodging in another downstream blood vessel didn't provide a benefit over using a stent alone in 626 Danish patients with ST-segment elevation MI. A month after implantation, no differences were seen between the groups in cardiac death, reinfarction, stroke, target vessel revascularization and major adverse cardiac and cerebral events.
EXACT revealed that high-risk patients can safely benefit from new embolus-removing and stent-inserting systems. The study tracked 1,500 patients in community hospitals who received carotid stent and/or embolic protection device treatments over 30 days and found that 4.5% suffered composite death, stroke or MI—better than the 7.5% found in a previous trial. Symptomatic patients had worse outcomes than asymptomatic patients.
The MATRIX Registry found that off-label use of sirolimus-eluting stents led to low two-year rates of complications and thrombosis. Of 1,521 patients, 34% had diabetes, 45% had prior percutaneous coronary intervention, 21% had prior coronary artery bypass grafting, 33% had prior MI and 46% had acute cardiac syndrome at baseline. Two years after stenting, rates of cardiac death, non-cardiac death, MI, target lesion revascularization and target vessel revascularization were 1.1%, 1.7%, 4%, 9% and 12%, respectively.
—Jessica Berthold
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