Are drug-eluting stents good or bad medicine? The question has been hotly debated since 2006, when a Swedish study indicated that the devices might be too risky to use in patients with complex coronary artery disease. Now a new pair of studies in the New England Journal of Medicine suggests another, more nuanced answer: the stents can be either good or bad, depending on the patient's needs. One of the studies, the first of its kind, pits drug-eluting stents against coronary artery bypass graft (CABG) operations and finds that the devices are not as effective as the surgery. (They are, however, equally safe in the long run.) The other study suggests that drug-eluting stents do have an advantage over another therapy: simpler, older "bare metal" stents. Together the studies suggest that doctors are closing in on an agreement for how and when drug-eluting stents should be used—a position that may put to rest the biggest cardiology controversy in recent years.
Stents are mesh tubes that hold coronary arteries open and improve blood flow to the heart muscle. Drug-eluting stents, which release heart medications, have been popular since their introduction in 2003, when the FDA approved them for use in a select group of patients: the "plain vanilla" ones, according to Dr. Donald Baim, medical director of Boston Scientific, a major manufacturer of the devices. Patients in the first trials of drug-eluting stents were relatively healthy. Some had only one narrowed artery, and generally the blockages in those arteries were small. The FDA's approval came with the caveat that the stents were appropriate only for these patients.
But doctors quickly and widely adopted the devices for "off-label" use in sicker patients, too. "They made the assumption that if the stents worked in the first group of patients, they'd work in others," says Dr. Oscar Marroquin, a cardiologist at the University of Pittsburgh and the lead author of one of the new studies. By 2005 somewhere between 50 and 70 percent of all stents were being used off-label in patients with multiple arterial blockages.
There was little reason at the time to think that was a bad thing. Before 2006 there were no studies to suggest that drug-eluting stents were inappropriate for treating serious disease. The devices were also appealing to patients in the current age of minimally invasive surgery. "Drug-eluting stents are much less invasive than CABG, so people who didn't want to be cut open and laid up for a long time favored them," says Edward Hannan, a health policy analyst at SUNY Albany and the lead researcher on the other new study. "There's also the fact that the gatekeeper—the physician who speaks with the patient about his options—was usually a cardiologist. Those are the doctors who put in stents. So cardiologists were in the position of advising the patient to undergo either the procedure they do or the procedure someone else does. It was a funny situation."
Then in March 2006 came the Swedish study—and with it what Baim likens to a "panic on Wall Street." The study showed that the long-term risk of death in patients with drug-eluting stents was 18 percent higher than the risk in patients treated with older stents, ones not coated in drugs that keep the vessels clear and open. It also suggested that drug-eluting stents might be causing potentially fatal clots in patients with complex arterial disease. Patients and doctors reacted with fear. Nationwide, enthusiasm for drug-eluting stents waned, a trend dramatically documented in the medical registries of New York state, which provided the data used in the new studies. Between early 2006 and early 2007 the number of patients in the New York databases treated with stents of any kind dropped by 12.5 percent, and the proportion of those stents that were drug-coated also dropped steeply, from 93.5 percent to 73.5 percent.
What was lost in the hubbub over the Swedish study was a simple, and in retrospect obvious, fact: the off-label patients in the study had always been sicker than the on-label ones. If they did worse with drug-eluting stents than the on-label patients, it could have been because they were worse off to begin with—not because of anything to do with the stents. The real question, says Marroquin, was whether the stents were "causing more problems than an alternative therapy." The Swedish study couldn't provide an answer to that.
The two new studies, however, can. The first of them is a head-on comparison of drug-eluting stents and CABG, which is the standard of care for complex coronary artery disease. Judging by the data, CABG shouldn't be unseated from that position; in many ways it's a better option than the drug-eluting stents. After 18 months patients in the New York databases who underwent the surgery needed fewer follow-up procedures. "With surgery you're most likely to treat all the arteries that are blocked," explains Spencer King, a past president of the American College of Cardiology and chairman of the New York state board that oversaw the new studies. "With stents you can have patients who only get one vessel opened, and later the symptoms will still be there." Patients who underwent CABG in the study were also less likely to die or have heart attacks, although the difference was "not whopping," says Marroquin—it was only about 2 percent.
The second study, unlike the first, does lend some support to the use of drug-eluting stents. It compares them not to CABG but to another option for treating coronary artery disease: bare metal stents. Here, drug-eluting stents are the winners: they're "as safe and more effective than bare metal stents in patients who have complex heart disease," says Marroquin, who led the study.
It's easy to assume that the studies suggest a clear hierarchy: CABG is better than drug-eluting stents, which are better than plain stents. That's largely true. But patients may still have a few reasons to keep drug-eluting stents in mind over CABG. Chief among them is the fact that bypass surgery is, well, surgery. The in-hospital mortality rate—in other words, the short-term risk—is higher for CABG than it is for the stents, although the risk evens out with time. "CABG is more invasive, so there are more things that can go wrong at first," says Hannan. "If nothing does go wrong, the surgical treatment has more promise for lasting a longer period of time—provided that the patient doesn't suffer a major complication during surgery and die."
There's also one group of patients who still should look at the third option, bare-metal stents: those who can't take clot-busting drugs. One such medication, Plavix, is usually administered before a drug-eluting stent is inserted. Patients who have a high risk of internal bleeding, or who are scheduled to undergo other surgeries, shouldn't take Plavix; bare metal may be their best bet.
Even though the new research is solid, it does not answer all the remaining questions about drug-eluting stents. Both papers are "observational" studies; they are not randomized controlled clinical trials, the gold standard for scientific research. Such trials of stents are difficult to conduct, says Joseph Carrozza, a cardiologist at Beth Israel Deaconess Medical Center in Boston who wrote an editorial accompanying the new studies. Potential patients are reluctant to enroll in trials when their lives may be on the line. "They have to be eligible for both stents and CABG," he says, "and most people don't want researchers making that decision for them based on the flip of a coin."
Wednesday's studies have also given researchers new questions to answer. Surprisingly, says Hannan, the CABG-versus-stent study showed that diabetics did equally well with bypass surgery and drug-eluting stents. Other studies have found that diabetics benefit more from surgery, even more than healthier patients do. "That issue definitely needs some further research," says Hannan.
Happily, further research is in store. Several other large studies of drug-eluting stents have been underway in recent years, and data from some of them will be revealed at conferences this summer and fall. The trials are sponsored largely by stent manufacturers, but they are also randomized and controlled. Combined with the studies released Wednesday, they may finally settle the debate.
Or not. Drug-eluting stents are still too cutting-edge to be fully appraised by doctors and scientists. Even with the new studies, no one knows what the long-term outcomes look like yet. "In three to five years we may be saying something completely different than what we're saying now," says Carrozza. "But you can't tell a patient to wait three to five years until we have all the information. We have to make these decisions today."