Matthew Herper and Robert Langreth 11.27.06
Twenty million Americans walk around with high-tech medical gear grinding away inside them. Are they safe?
Johnson & Johnson's drug-coated stent is a miracle of medical engineering. The tiny, stainless-steel mesh tube, less than 4 millimeters wide, relieves the crushing chest pain that occurs when the heart is starved of blood. Covered in a chemical that keeps the artery from closing, the stent slides into a blocked vessel in a simple, not very invasive procedure and stays there, propping it open. After it hit the market in April 2003, cardiologists implanted the new stent in 350,000 people in eleven months, though it costs nearly three times as much as older, noncoated versions.
Since then drug-coated stents from J&J and Boston Scientific have been inserted into the arteries of 4 million people. The breakthrough medical devices generate $5 billion a year in sales from a million patients. You might figure that, being federally regulated, these devices were approved only after the manufacturers established both their safety and their efficacy. But that's true only up to a point. It turns out that the teensy tubular scaffolds have never been shown to prevent heart attacks or save lives; their human trials were smaller, of shorter duration and more narrowly focused than trials for many new drugs; and half of all applications involve "off-label" uses, deploying stents in ways that weren't studied at all in clinical testing.
Now new data indicate that the stents, because of their supposedly miraculous coating, may cause 4,500 heart attacks every year, up to 2,000 of them fatal. This increased risk, moreover, could persist for a lifetime, requiring patients to take blood thinners for the rest of their lives, thereby facing the sometimes fatal side effects of those drugs.
"There's so much evidence" of the new danger, says Spencer King, the Piedmont Hospital cardiologist who in 1987 implanted the first stent in North America. He says up to 30% of patients who get drug-coated stents would fare better with bare metal, avoiding extra heart attack risk; some probably didn't need a stent procedure at all. "Everybody agrees this is real," he says.
But Johnson & Johnson insists it sees no significantly increased risk. Boston Scientific says the worries are overblown. It and many researchers say the drug-coated stents' ability to vastly reduce reclogging outweighs the risks. Next month the two gadget giants will have to defend their thriving business before an expert panel advising the Food & Drug Administration on the issue. Whatever the outcome, can plaintiff lawyers be far behind?
The flap over stents is the latest in a series of safety scares now racking the booming, $80 billion-a-year business of medical devices. Some 20 million Americans now walk around embedded with high-tech gear: artificial hips and knee joints, pacemakers, heart defibrillators and more. Most of the 80,000 gadgets in use--and most of the 4,000 new ones okayed every year--are safe and effective.
But 79 devices have been yanked off the market in the past five years because of potentially fatal side effects, up 65% over the previous five years; 2,300 more gadgets have been recalled for lesser complications. And when a recall happens, often the suspect device remains inside patients.
Implantable defibrillators, which deliver a shock to the heart to prevent it from shutting down, have been surgically implanted into hundreds of thousands of patients in recent years. Then in 2005 defib maker Guidant told doctors about a design flaw that could render two of its models ineffective--three years after it first spotted the problem. Some of the 40,000 patients with these models underwent surgery to replace them, while others wait for what might go wrong. The manufacturer, now owned by Boston Scientific, faces 550 individual or class suits. Cardiologists say that the number of malfunctions is small compared with the number of lives saved.
Guidant also took a hit in 2003 over its Ancure aortic stent. Approved in 1999 after trials involving 621 patients, it was created to thwart aortic aneurism, a weak spot in the main artery from the heart. (If the aneurism bursts, the patient could die.) Guidant soon learned the delivery system sometimes got stuck in blood vessels during installation. But instead of reporting all of the problems to the FDA, as required, the company initially kept it quiet. In two years the new stent went into some 7,600 patients--and malfunctions occurred in more than 2,600 of the cases, leading to 12 patient deaths, the Justice Department says. After seven whistleblowers alerted the feds, Guidant pleaded guilty to ten felonies, paid a $92 million fine and shut down the business making the aortic stent.
Now some doctors are flagging the potential dangers of new implantable gadgets to treat back pain, prevent stroke and soothe severe heartburn. Some doctors decry J&J's new metal disc, known as the Charite, which has been implanted in the spines of several thousand patients. It was approved by regulators after a trial involving only 304 patients--and only 36% of them fared well enough to get off narcotic painkillers.
Neck stents made by Abbott Laboratories are coming into question, too. They can prevent strokes by propping open the carotid artery, letting patients avoid the usual practice of having that vessel cut open in surgery. But in October a 527-patient study sponsored by the French government found that 10% of patients who got neck stents died or had a stroke in the following month--double the complication rate for surgery. Abbott says its studies show no added risk, and one supporter, German cardiologist Klaus Mathias, says the French study was the most poorly run clinical trial he had ever seen. Abbott is conducting trials in 4,000 patients to settle the matter.
Another much-debated fix: tiny clumps of polymer lodged in the esophagus to quell heartburn. Boston Scientific's Enteryx spurts a polymer into the throat to alleviate pain. It was approved in 2003 after being tested in FDA trials in a mere 109 patients over 12 months. (By comparison, 11,000 patients took Wyeth's ulcer pill, Protonix, for the same amount of time in order to get the drug approved.)
But the plastic-dispensing device was difficult to use properly. Sometimes doctors delivered the polymer to the wrong place, causing internal bleeding and kidney damage. One patient bled to death when the chemical was injected into the aorta instead of the esophagus. The company voluntarily pulled the device in 2005.
Several competing heartburn gadgets remain on the market, despite limited testing. "These things were rushed to market too early, without being tested enough," contends gastroenterologist Walter Hogan at the Medical College of Wisconsin, who calls for a moratorium on their use until better studies are done.
More safety questions may arise with increasing frequency. Hundreds of clinical trials are under way for still more miracle gadgets: new devices to treat depression by using magnetic fields applied to the skull; replacement parts for bad heart valves; a mesh bag that is wrapped around the heart to help counteract heart failure.
Some doctors, academics and patient advocates blame the lapses on a medical-industrial complex made up of acquiescent regulators, gadget-happy cardiologists and surgeons who rake in consulting and appearance fees from device makers, and pushy device makers themselves. These critics cite an overly lax regulatory process, trials that are far less demanding than those for drugs and a lack of follow-up after treatment.
Some devices "haven't been as safe as they should be," says David Waters, a cardiologist at the University of California, San Francisco. "It's just easier for something that doesn't work well to slip by." Charles Rosen, a spinal surgeon and safety crusader at UC, Irvine, adds: "The FDA isn't meeting its responsibility to ensure the safety and efficacy of devices for the American public. [Regulators] are manipulated by industry." Says Eric Sacks of Emergency Care Research Institute, a nonprofit that tracks recall data: "The system is overwhelmed."
The FDA admits as much, acknowledging "inadequacies" and "shortcomings" in tracking device safety and vowing to overhaul its approach. "I don't see this as a bad thing--I see it as good," says James Tobin, chief of Boston Scientific, of efforts to more thoroughly test devices. The device industry trade group, AdvaMed, says the FDA "does a good job" and that makers are helping it "streamline and refine postmarket reporting mechanisms."
That is an elusive quest, given the swelling ranks of gadget patients. Each year half a million people in the U.S. undergo spinal-fusion surgery, says research firm Frost & Sullivan. They get cages, screws and rods implanted in the spine, despite studies that show fusion is not very effective for lower back pain. A total of 160,000 Americans get artificial hips made of titanium and plastic; 280,000 get knee replacements; a quarter-million get defibs. Only one implantable-defibrillator patient in five ends up needing a jolt to the heart. To be sure, you don't know in advance which patients will need this life-saving jolt.
This thriving trade in man-made body parts has enriched shareholders of device makers: An index of 11 such stocks is up 43% in four years, while a drugmaker index has fallen 2%, hurt by the Vioxx safety scandal and other travails. The gadget craze has created several fortunes, making billionaires of William Cook of Cook Group, who used a blowtorch to make an early catheter, and John Abele, cofounder of Boston Scientific.
The device boom also has fattened the wallets of thousands of physicians. The advent of angioplasty created a new breed: the interventional cardiologist--14,000 of them. Elsewhere 3,500 doctors specialize in implanting parts for aching backs.
The symbiosis between docs and device makers concerns some experts. "Physicians like to do things that work, that make money and promote their specialty," says Frank Veith, a vascular surgeon at New York University Medical Center who is critical of newfangled neck stents.
The industry's ties to docs are so cozy that at a recent conference on "Trans-catheter Cardiovascular Therapeutics," in Washington, D.C., the hosts put out a booklet disclosing conflicts of interest. It ran on for 45 pages. Many researchers disclosed having accepted thousands of dollars in research grants and consulting and speaker fees. The organizer, cardiologist Gregg Stone of Columbia University, revealed that 12 companies had each paid him $10,000 or more and that he had taken equity stakes in 11 more. Stone says working with industry leads to advances that help patients.
UC, Irvine's Charles Rosen argues that scores of spine surgeons "have basically become marketing men for these companies and earn huge consulting fees."
"It is a rigged system," Rosen laments. He has formed the Association of Ethical Spine Surgeons for physicians who are free of such conflicts; 50 have signed up.
Now the feds are stepping in. Medtronic in July agreed to pay $40 million in fines to settle civil allegations that its spinal-devices unit paid kickbacks to doctors in the form of sham consulting agreements, shady royalty pacts and lavish trips; though the company paid up, it denies any wrongdoing.
Some patients feel betrayed. Catherine Rich, 40, of Mission Viejo, Calif., endured debilitating back pain for three months before following her surgeon's advice to let him embed her spine with an $11,500 disc from J&J. "It was presented like it was going to solve all my problems. I was going to be this bionic woman," she says. But her agony returned, worse than ever--she couldn't go to work, care for her 4-year-old son or have sex with her husband.
So Rich had to undergo a second surgery, this one performed by Dr. Rosen. He argues that J&J's Charite disc increased her pain, but he left it in place and fused together two vertebrae. Rich says she still can't climb stairs easily and spends 23 hours a day in a special hospital bed. "It ruined my life." So far she hasn't sued--but at least 30 other disc recipients have.
Rosen believes hundreds more patients have been hurt by the new disc, which has been implanted in several thousand people. (He has done some limited work reviewing cases for plaintiff lawyers.) Rosen contends J&J's trial compared Charite with an outmoded surgery to make the metal disc look more effective.
J&J denies the trial was rigged and insists the Charite disc has a low complication rate and that it lets patients recover faster than when they undergo older fusion surgery; only 8% of 688 patients it studied needed repeat operations. Texas Back Institute spine surgeon Richard Guyer concurs, citing results in more than 300 patients at his clinic. The vast majority "are very happy," says Guyer, who receives consulting fees from J&J.
Making myriad metal parts for ailing spines now is a $2.3 billion-a-year business, Frost & Sullivan says, growing 25% a year. The number of lumbar fusions, to name one procedure, tripled from 1990 to 2001, reaching 120,000 that year. "Most spine devices are of uncertain efficacy and probably add to the complication rate," says internist Richard Deyo at the University of Washington. He studied spinal-fusion surgeries in Washington State and found that as procedures soared from 1990 to 2000, the rate of repeat surgeries rose a bit; it would have fallen had the devices worked well.
But critics who assert there is no data supporting back surgery are "flat-out wrong," says spine surgeon John Peloza of Dallas. "Surgery is expanding because the technology is so much better." He adds that no progress would be made if device makers and doctors didn't work closely together. Spine device maker Medtronic says back surgery "has proven results."
The booming industry's humble beginnings go back a century. In 1886 J&J opened up shop in New Brunswick, N.J. on the fourth floor of a former wallpaper factory; 14 employees made sterile surgical dressings. In the late 1950s and early 1960s came the first artificial hips, developed by British surgeons, and then the first artificial heart valves. The first pacemaker that could be implanted in patients came about the same time, from a then tiny firm called Medtronic.
The modern device era exploded in 1977 with the invention of angioplasty, when German cardiologist Andreas Gruentzig made a tiny slice near the hip of a patient and inserted a catheter tipped with a balloon into an artery. He snaked it up into the heart, inflating the balloon to squish a clump of plaque against the artery's inner wall to clear it.
The new procedure led to the founding of Boston Scientific in 1979. Around the same time the implantable defibrillator was invented, building Medtronic and St. Jude Medical. Angioplasty, defibs and orthopedics are now mainstays of the device industry.
The industry was barely regulated until 1976, when Congress empowered the FDA to ensure devices were safe, effective and well made. But the new law included a loophole called 510(k) that remains today: A device can be approved with few or no clinical trials if it is deemed "substantially equivalent" to a gadget that existed before 1976.
Most of the thousands of devices in use today were cleared under this easy passage, even frightfully intrusive new tools. In 2004 Concentric Medical of Mountain View, Calif. unveiled one of the first devices to treat stroke, a kind of corkscrew for the brain. It is fed from a slit in the groin into the neck to clear out the vessel and then is removed. It was approved via 510(k) because it was similar to older devices.
But some neurologists say it has not yet been proved to help patients recover from stroke, even as stroke drugs with better data were turned down. "It is very frustrating. Approving this device has made it difficult to find out how well it works," says University of Pittsburgh neurologist Lawrence R. Wechsler. Concentric counters that it now is running a federally funded trial of 120 patients.
Another device, the Aquadex FlexFlow from CHF Solutions of Brooklyn Park, Minn., is used as an alternative to drugs to drain excess fluid from patients with congestive heart failure. The Aquadex sits outside the body like an intravenous bag, cycling healthy blood back into the patient. It cleared the FDA on a 510(k) exception in 2002. By contrast, a J&J drug to treat the same problem endured 14 clinical trials covering more than 1,500 patients--and still drew fire for safety questions. CHF has new results from a 200-patient study that seem to show the FlexFlow, which costs $14,500, has some advantage over drugs--four years after it went on the market.
The FDA looked at tightening device rules in the early 1990s, but Congress undercut the effort. To be sure, it is possible for regulators to go too far in regulating implants. In 1992 the agency called a moratorium on silicone breast implants, playing into the hands of tort lawyers making an industry of suing silicone implant maker Dow Corning. After the company was bankrupted by the litigation it became apparent that there was scarcely any scientifically established link between silicone and the health problems blamed on it. Dow Corning is now out of bankruptcy. Breast implants may return to the market by next year.
In 1993 a high-ranking FDA official, Robert Temple, issued a report on how the burgeoning device industry could conduct more rigorous clinical trials. That faded in 1997 when Congress passed a law dictating that new devices must be approved by the "least burdensome" method possible.
By that time the industry had gotten a big boost with the first metal stent for clogged arteries. Doctors were doing 300,000 balloon angioplasties annually in the U.S., but in upward of 40% of cases the artery reclogged (a process known as restenosis). To combat this, J&J in 1994 introduced the first stent to prop the artery open; this cut restenosis to 15% of cases. Angioplasties soared to 800,000 a year by 2002. Then came J&J's drug-coated stent, which reduced the reclogging problem to fewer than 5% of patients, and angios increased to more than a million a year.
The new stent, the Cypher, was tested on 1,058 patients in its biggest trial; a heart-drug study might require three times as many subjects. The tiny tube was coated in a rubbery polymer that released bits of medicine over time, preventing the artery from growing scar tissue over the device and reclogging the blood flow. But that left the polymer and metal exposed, and in rare cases blood clots form on this foreign surface and cause heart attacks.
Patients with drug-coated stents get clots at the rate of 1 per 500 patients per year, to judge from outside analyses of the company's trial results. J&J and Boston Scientific will be running trials of tens of thousands of patients to better understand the blood-clot risk, but results won't be available for years.
Many doctors argue that the FDA should toughen its standards for introducing new implants of all kinds. But doing so might slow innovation in a breakthrough-fueled industry. "The device industry would grind to a halt" if studies for implants became as big as those for drugs, says Mitchell Krucoff of the Duke Clinical Research Institute. Thomas Fogarty, a professor at Stanford who has patents on 63 devices, says young doctors are reluctant to invent new devices because of the regulatory scrutiny they already face. "We in the U.S. are slowing down and losing our position of leadership," he frets.
Daniel Schultz, the FDA's chief device regulator, says new medical devices don't need the large-scale exhaustive trials of the drug industry because it is easier to predict the behavior of a machine than it is to track the chemical interactions of a new drug in the body. But he vows to pursue sweeping changes in how the FDA monitors device performance after approval, creating a massive database to track all "adverse events" far faster than today's paperwork reporting process can.
"We are talking about fundamental changes," Schultz says. He emphasizes that the benefits of medical devices "far outweigh any risk." The hard part: sifting out the few flawed devices that emerge in this surging business of bionic parts--and stopping them from posing hidden threats to millions of patients.