In the wake of recent concerns about the long-term safety of drug-eluting stents (DES), including presentations last month at the World Congress of Cardiology (WCC; Sophia Antipolis, France), an editorial published last month on the web site of the American College of Cardiology (ACC; Washington) will likely add fuel to that fire. It charges that 2,000 patients are dying needlessly each year as a result of DES use.
The guest editorial, “Drug-eluting stents: An Ounce of Prevention for a Pound of Flesh,” said patients face a lower risk if treated with older, bare-metal stents (BMS) that might work, in many cases, just as well.
Written by Sanjay Kaul, MD, and George Diamond, MD, of Cedars-Sinai Medical Center (Los Angeles), this is the latest expression of concern about the risks of fatal blood clotting and serious heart attacks associated with DES.
”I think the debate here is not the drug-eluting stent vs. the bare metal stent,” Kaul told Cardiovascular Device Update. “There’s a bigger debate here, and that is our obsession with revascularization as the primary therapy for treating stable angina.”
He said that drug therapy should be the first avenue for treating chronic stable angina “and only in those who don’t respond to [drug] therapy should revascularization therapy — whether stenting, angioplasty or bypass surgery — be offered.” He said that in a “quick fix society,” patients demand that approach, and “we are too eager to please them.”
In the U.S., the devices are sold by Boston Scientific (Natick, Massachusetts) and Johnson & Johnson (New Brunswick, New Jersey) via its Cordis (Miami Lakes, Florida) business.
Kaul said that research suggests the use of the DES increases the risk of clotting by 0.6% annually, compared with BMS-implantation. With more than 1 million Americans annually receiving the stents, and at least 80% of them getting DES devices, this works out to an additional 2,160 deaths each year, the doctors calculated. The figure assumes that 45% of the people who suffered such clots had died.
“It’s eerily reminiscent of Vioxx,” Kaul told the New York Times, referring to the popular painkiller that Merck (Whitehouse Station, New Jersey) withdrew from the market in 2004 after being linked to heart attacks. “Initially we didn’t see the signal because the incidence is so rare.” Kaul said that use of DES is proper treatment for many patients, but that they are used far too often in cases where clinical data suggests that BMS use or long-term drug therapy is safer. Only about 20% of DES devices are being inserted in patients who have the kinds of conditions studied in the clinical trials that led federal regulators to approve them, he said.
Kaul told CDU that he is, by nature, a skeptic and that he never got caught up in the DES hype. He noted that the clinical benefits of DES relative to restenosis and target vessel revascularization (TVR) have been overestimated. For example, he said the TVR rates in the BMS control group were nearly 50% higher in the DES trials than that observed in contemporary interventional trials or in “real-world” clinical practice.
Kaul said he attributes the too-rapid integration of DES into clinical practice in the U.S. to a perfect storm of factors: device companies seeking larger profit margins to support the expense of clinical trials, regulatory approvals and marketing; the pressure of career advancement via rapid research and publication; the drive to feed insurance companies with the data that will drive reimbursement; and hospitals, physicians and patients all wanting cutting-edge treatments and technologies.
“Together,” the authors write, “all these individually understandable incentives conspire to introduce promising new technology too quickly into the medical marketplace and to encourage its rapid overutilization. It is not at all surprising then that conflicts should exist between clinical practice and its evidentiary support, and that many DES interventions are thereby insufficiently justified. ... [I]t appears that the rules regarding use of DES, while justifiable to combat the knotty problem of restenosis (‘an ounce of prevention’), have inadvertently led to the new and even more intractable problem of late stent thrombosis (‘a pound of flesh’).”
Kaul noted declining use of DES at his hospital, from 95% a year ago to about 80%, “and continuing.” He said the “real world restenosis rate” is not nearly as high as the off-label uses of the devices would indicate, and that the real rate of use of these devices should be in the 10% to 15% range — even lower than the 20% approved by the FDA — as a “bail out” for those patients who present with restenosis following BMS.
These numbers, he said, may further be reduced since those patients who are unable or unlikely to comply with the long-term dual antiplatelet therapy necessary with these devices “should never be given a drug-eluting stent.” He also suggested that for left main disease and multivessel disease, especially diabetics, coronary artery bypass surgery should remain the treatment of choice, until randomized data prove the effectiveness and safety of DES in these conditions.
Other doctors appear to be backing this trend. Merrill Lynch analyst Katherine Owen published a survey of 50 interventional cardiologists who implant the devices, finding that 42% said they may implant fewer DES devices, and 30% were still waiting for more evidence before making a decision. Based in part on those responses, Owen cut her expected penetration of DES in the 2007 U.S. market to 80% from a previous projection of 85%, or to $2.74 billion in sales from $2.92 billion.
Dual-magnets/stenting used for drug delivery
The use of magnets in a device for the targeted delivery of drugs is nothing new. For example, FeRx, which had been based in San Diego, developed what it called Magnetic Targeted Carrier Technology which employed a small, externally positioned magnet, combined with microparticles made of metallic iron and activated carbon. The microparticles were mixed with a drug and the magnet was then positioned to draw the drug to a specific site in the body. FeRx discontinued operations in 2004 after its major trial failed to reach significance in the treatment of primary liver cancer.
Now, researchers reporting at the Annual Congress of the American College of Surgeons (Chicago) have described a new spin on this delivery method — using magnetism, incorporated into an implanted stent, and pairing this with an external magnet. The study, the researchers said, provides proof of principle that the dual-magnet sources, in tandem, can deliver drugs to a targeted area and do it efficiently.
“We haven’t reinvented the wheel yet, but we are getting very encouraging results,” said Zachary Forbes, PhD, assistant professor of surgery at Drexel University College of Medicine (Philadelphia).
The investigators said they believe the method may be tailored to carry antibiotics used to prevent acute and chronic infection and to confine chemotherapeutic agents to malignant tumors. Their first objective, however, is to adapt the system for use in preventing restenosis of the arteries.
Forbes and colleagues magnetize basic cornoary stents so that magnetic nanoparticles treated with drugs can be delivered directly to areas of infection or inflammation. The researchers either added a thin layer of magnetic material to a standard stent or incorporated into it a magnetic alloy that will draw drugs armed with magnetic particles to the implants.
The researchers inserted into animals stents that had been composed of an alloy that magnetized the implants without interfering with their mechanical integrity or properties. After magnetic particles were injected and allowed to circulate in the bloodstream, the investigators computed the number of particles captured by the stents and determined the pattern of distribution of the particles in the tissue.
The researchers found that the magnetic forces generated by the stents attracted enough nanoparticles to be therapeutic, and the stents held magnetic nanoparticles in the bloodstream in a characteristic pattern.
“This system of drug delivery could be used for long-term healing by magnetically attracting particles to the stent, thus providing a sort of rechargeable drug delivery over the life of the implant. Instead of having to restent a blood vessel or perform bypass surgery, patients may be treatable simply by magnetically dosing a site with a given drug,” he said.
The researchers contrasted the system to methods using only external magnets, such as in the approach by FeRx. “Those systems could get particles to the right site, but had difficulty distributing the particles when they got there,” Forbes said. “So the particles ended up in clumps or scattered over a couple of inches instead of staying in one place.”
Developed for humans, the magnetic stent would be inserted placed at a designated site, via catheter, in the cardiovascular system. The external magnetic field would lead magnetically charged drugs to the stent, and the stent would hold the drugs in place.
Forbes said, “The kinds of doses we are using in our first studies translate very well to the kinds of numbers of particles we would want to have in the human body. So the fact that we have control over our particles means we have a much more efficient way of putting a certain amount of a drug on a designated surface area.”
Cardio health promotion impact limited
Health promotion counseling, education and drug therapy have been shown to reduce some coronary risks but have no real impact on mortality or disease in large groups of people, according to a report led by Dr. Shah Ebrahim, a professor of public health at the London School of Hygiene and Tropical Medicine. The researchers reviewed 39 studies involving about 140,000 patients. They found some positive results, but these did not translate to reductions in morbidity and mortality, Ebrahim said.
Of the studies, the clearest benefit seen was with the use of drugs for lowering blood pressure and cholesterol, and interventions may be beneficial for selected populations, Ebrahim said. People at low or moderate risk may also benefit, but whether this is cost-effective may vary from case to case.
“More intensive interventions might be expected to produce better effects, but those used in many of the trials would far exceed what is feasible in routine practice,” Ebrahim said.