Drug-eluting stents – safe and effective?

Despite their growing popularity, drug-eluting stents have been linked with infrequent but severe side effects including increased risk for cardiac-related deaths, and thrombosis.

Compared to alternative treatments, however, Dr. Gregg W. Stone, Professor of Medicine at Columbia University Medical Center and Chairman of the Cardiovascular Research Foundation, says the data collectively available to date suggests they are safe and effective for most patients requiring coronary angioplasty.

In 1986, the first stent was inserted into a human coronary artery in France. Eight years later, it was also approved for use in the US. Although stent technology was revolutionary, there were serious concerns about early stent technology, which caused the delayed introduction in the US. Dr. Gregg W. Stone, Professor of Medicine at Columbia University Medical Center and Chairman of the Cardiovascular Research Foundation (CRF), recalls: “There were major issues with stent thrombosis early on, 20 percent in the initial studies, which required intensive pharmacologic regimens to be able to suppress the rate to three to four percent. However, that introduced new complications, including excessive bleeding and prolonged hospital stays.” Nonetheless, large scale randomized trials were performed which demonstrated that compared to balloon angioplasty, stents were overall safe and effective, and truly did represent an advance. That’s when the FDA approved their use in the US.

It was due to innovations by Antonio Colombo and others that stent thrombosis rates could be reduced to the one percent level. The importance of adequate stent implantation was demonstrated with intravascular ultrasound guidance, and the aspirin and coumadin based regimen was switched to aspirin and a thienopyridine, initially ticlopidine. As a result bleeding and vascular complications were markedly reduced and patients could be discharged from the hospital the next day. The essential role of dual antiplatelet therapy with aspirin and ticlopidine to prevent stent thrombosis in most patients were later confirmed in numerous large randomized trials.

Stent thrombosis

Bare metal stents constituted an amazing advance in that they overcame many of the problems of balloon angioplasty, including the high rate of dissection resulting in frequent abrupt or subacute vessel closure requiring emergency coronary artery bypass graft surgery. In addition, balloon angioplasty was associated with a high rate of restenosis in the order of 40 to 50 percent due to a combination of excessive neointimal hyperplasia and constrictive negative vessel remodelling. The consequence: repeat procedures within six months. Stents, says Stone, significantly addressed at least two of the major three problems by providing a mechanical scaffold. “The acute closure rate was essentially eliminated because no significant dissections remain after a stent is placed, and the greater luminal dimensions with stents compared to balloon angioplasty reduced the rate of restenosis by about one third. However, two ongoing issues with stents were stent thrombosis, which occurred in 0.5 to one percent of patients, frequently resulting in death or large myocardial infarction; and restenosis, which, still occurred in 20 to 30 percent of patients.”

Drug-eluting stents (DES) were developed as the solution to restenosis. Designed to deliver an agent to the area of local vascular injury, DES inhibit the amount of neointimal hyperplasia that forms, thereby reducing restenosis. The first drug-eluting stent, the sirolimus-eluting Cypher stent, was approved in the US in April 2003. The approval of the second, the paclitaxel-eluting Taxus stent, followed one year later in March 2004. Within a year, they rapidly experienced wide-spread use. DES were being used in more than 70 percent of cases, with a peak of use in 85 to 87 percent of cases in mid-2004.

The main benefit of drug-eluting stents is to prevent restenosis. Dr. Stone explains: “For the types of lesions in which they have been thoroughly studied, mostly single non complex lesions in native coronary arteries in patients primarily with stable coronary artery disease, both DES have been shown to be overall safe and effective. They markedly reduce restenosis rates by probably 50 to 75 percent, and subsequent target lesion revascularization, while having similar overall death and myocardial infarction (MI) rates compared to their bare-metal stent counterparts. The late stent thrombosis rates are slightly increased with both the sirolimus eluting and paclitaxel eluting stents that are approved in the US in these lesions, in approximately 1 out of 500 patients per year. But that doesn’t translate into an overall incidence of death and MI likely because the prevention of restenosis by DES, which occasionally presents or results in death and/or MI, offsets this risk. Patients and physicians alike have been gratified by the reduction of restenosis, which translates into less angina and medication requirements, better exercise capacity, fewer hospital readmissions for repeat angioplasty or surgery, and an overall better quality of life”

Off-label concerns

Still, the major concern DES remains stent thrombosis, especially when used “off-label”, in more complex and high risk situations that those studied in the pivotal randomized trials. Stone: “Concerns have been raised that when used off-label, that is in some of the more complex patients and lesions, stent thrombosis rates, especially the late thrombosis after 6-12 months, may be increased compared to those seen in simple lesions. Anywhere from 0.2 to 0.6 percent per year. However, there are no control populations for the most part to say how bare-metal stents or alternative therapies such as medical therapy or surgery would have done.”

Several large registries have examined whether or not drug-eluting stents in off-label use are more or less safe and effective than bare-metal stents. The results of these studies in “real-world, unrestricted patient populations” have been mixed to date. Stone: “The Swedish SCAAR study in approximately 20,000 patients suggested an increase in late mortality and possibly MI with DES use – this observational study received a lot of media attention. In contrast, registries from Rotterdam, Wake Forest Medical Cerner, and the STENT study group in the U.S. suggest that DES compared to bare metal stents are associated with reduced early and late mortality – the press have been less interested in these reports.”

Three large-scale currently ongoing randomized trials are specifically examining the safety and efficacy of DES in complex and high risk patients. The Horizons Trial, of which Stone is the principal investigator, compares drug-eluting stents to bare-metal stents in acute MI in 3600 patients. Two other large-scale trials are looking at drug-eluting stents compared to bypass surgery. The first, called Freedom Trial, investigates DES use in patients with diabetes and double- or triple-vessel disease compared to surgery. The second trial, Syntax, compares Taxus stents to surgery in patients with unprotected left main or triple-vessel disease. “Four randomized trials have convincingly demonstrated that DES should be the treatment of choice for most patients with bare metal stent restenosis. Multiple small and intermediate sized randomized trials have also been completed demonstrating that DES are may be effective in patients with saphenous vein grafts, unprotected left main disease, chronic total occlusions and high risk patients with acute myocardial infarction. However, those studies were all underpowered for safety and as such definitive practice-based recommendations aren’t possible. We need to see the complete data from the large-scale randomized trials before the use of drug-eluting stents can be generalized to the highest risk and most complex patients, such as acute MI, left main disease and complex multivessel disease.” concludes Stone.

There are other potential adverse effects with drug-eluting stents beyond stent thrombosis. The polymers can induce hypersensitivity reactions, which may contribute to lack of healing, late restenosis or stent thrombosis. Strut fractures may also lead to restenosis and possibly stent thrombosis. There may be downstream vascular effects leading to vasospasm. Drug-eluting stents may also occasionally cause aneurysm formation, and positive remodelling can result in late acquired stent malapposition. Yet despite this long list of adverse events, Stone is convinced that the benefits weigh out the risk factors: “Overall, for the types of lesions that have been approved by the FDA, paclitaxel-eluting TAXUS and sirolimus-eluting Cypher stents have clearly been proven to be very effective and safe, with a similar overall safety profile in terms of the hard end points of death and MI compared to bare-metal stents. The question arises now about off-label use, and most of the randomized trials and registry reports have been supportive that DES are safe and effective in more unrestricted use. However, we need more data in many more patients followed for years before we can be certain. Finally, it is critical that patients receiving DES be able to take at least 6 months and in most cases at least 1 year of dual antiplatelet therapy. This issue must be discussed with each patient at length. Patients unable to comply, or in whom planned surgery will necessitate medication discontinuation should not, in most cases, receive DES.”

Prevention

Alternatives to stent-based therapy for patients with coronary artery diseases are medical therapy and coronary bypass surgery. Significant advances, says Stone, have occurred in both areas concordant with advances in stent technology: “Medical therapies are much better than they were 20 years ago. Aspirin, statins and anti-anginal medications are adequate for some patients with mild angina, but coronary revascularization with angioplasty will clearly reduce symptoms, prolong exercise duration and enhance quality of life for most patients with significant angina. Patients with unstable angina and acute myocardial infarction have clearly been shown to have lower mortality and greater freedom from MI, refractory ischemia, rehospitalization and stroke by an early invasive approach compared to more conservative medical therapy or fibrinolysis. Bypass surgery continues to improve with robotic and minimally invasive approaches and is an excellent option for patients with severe and complex coronary artery disease. In the future, advanced pharmacological adjuncts and device based improvements based on molecular cardiology advances and new personalized medicine approaches with genetic profiling are going to improve our ability to predict which patients will respond to which therapy.”

Equally important, adds Stone, is prevention. Safer and more effective drugs to reduce high blood pressure and control hypercholesterolemia are already available. And Stone lists more: “Most people know that low dose daily aspirin is the least expensive way to prolong life. And clopidogrel has a role in certain patients with extensive vascular disease as well for secondary prevention. We still need to control risk factors, and generate more definitive proof about the efficacy of tight glucose control in patients with diabetes. There will be increasing access to mechanical approaches such as insulin pumps with automatic internal feedback loops to regulate blood sugar. There is still hope for HDL raising therapies and other approaches to hypercholesterolemia. We need drugs that are safer and easier to take, which have less side effects. Stents can only take us so far in reducing cardiovascular mortality.”

Obviously, says Stone, smoking continues to be a scourge on society, although it is probably the most directly preventable cause of cardiovascular disease, lung disease, and cancer. And despite all medical and technological advances, a growing obesity epidemic is adding to the number of preventable deaths. Stone: “From a cardiovascular point of view, we are getting somewhat healthier but we could do a lot better. Cardiovascular mortality and case fatality rates from MI over the last 25 years in this country have been plummeting. We have made fantastic advances with coronary care units, reperfusion therapy and primary and secondary preventative strategies. Patients are living longer, but this means that cardiac disease is often symptomatic at a more elderly age, which of course makes management more difficult and high risk. Ironically, the elderly and high risk patients, those who have the most to gain by advances in medical care, are often under-treated. We have made great strides in the treatment of heart disease but we have a long way to go.”

Dr. Gregg Stone: “Dr. Gregg Stone is a professor of medicine at Columbia University Medical Center and Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapy at New York Presbyterian Hospital. As Chairman of the Cardiovascular Research Foundation, Stone is devoted to researching interventional lesser invasive vascular therapies, and educating physician organizations and individuals about those topics.”

Dr. Gregg Stone: “Most people know that low dose daily aspirin is the least expensive way to prolong life.”

Dr. Gregg Stone: “We need drugs that are safer and easier to take, which have less side effects. Stents can only take us so far in reducing cardiovascular mortality.”