A seven-year US study has called into question whether doctors are overusing heart stents, the blockbuster tiny wire mesh tubes used to prop open narrowing coronary arteries.
The results of the study, called Courage, added more uncertainty to a stent market that recently has been thrown into flux over questions of safety, appropriate usage and new competition.
This flux was also highlighted by a 7 per cent fall in the share price of Boston Scientific, a leading US stent maker, because new data showed a forthcoming stent by rival Abbott Laboratories could be better than its most important product, Taxus.
Debate has swirled among the medical community, regulators and device-makers, raising questions over the past year on whether medical devices have been used too soon and too aggressively.
Drug-coated stents, whose coating helps keep arteries from scarring and closing again, have been at the centre of that debate as one of the most widely used devices.
Medical devices are increasingly feeling scrutiny, akin to that seen with pharmaceuticals, from doctors and US regulators concerned with potential emerging questions about long-term safety.
In addition, as use of expensive devices has increased markedly, more scrutiny has fallen on the relative benefit of new medical devices. For instance, a recent Food and Drug Administration panel recommended against approval of a implantable heart data monitor by Medtronic, a US group, that could transmit patient data to a doctor via the internet.
The Courage study, presented on Monday at the annual American College of Cardiology meeting, looked at whether people receiving stents and drug therapy had fewer deaths or heart attacks than those with drug therapy alone.
Importantly, the study sought to find out if stents in patients with stable coronary artery disease whose life was not acutely threatened reduced risk of death and heart attacks because such a benefit "had not been shown".
The study said that, in 2004, more than 1m stents were implanted in the US and 85 per cent were done so in patients with stable disease.
The Courage study found "no significant differences" by using bare-metal stents as compared with drug therapy alone, in death, heart attacks or stroke. It did find that patients with stents had fewer chest pains.
Tuesday, March 27, 2007
Angioplasty no better than drugs, study says
A large and long-awaited study finds that angioplasty works no better than medication at preventing heart attacks or death, a finding that could slow the growth of one of medicine's most common cardiac interventions.
The research comes on the heels of a growing debate over whether some patients are getting unnecessary angioplasty, a procedure that involves using a tiny balloon and metal scaffolds called stents to prop open clogged arteries.
Angioplasty is recommended for those with fully blocked arteries or who have had a heart attack. But the new study, presented at the American College of Cardiology's annual meeting in New Orleans yesterday, should give doctors and their patients with partially obstructed arteries the confidence to put off angioplasty or to skip surgery altogether, according to the researchers.
"The results are very striking," said Dr. Steven Nissen , president of the American College of Cardiology, who was not involved in the study. "This is important for patients because it does now mean patients have choices. If your symptoms aren't so severe and aren't interfering with your lifestyle, you can afford to wait."
Half of the 2,300 patients studied underwent angioplasty and took heart drugs, and were told to make lifestyle changes, such as exercising, losing weight, and giving up smoking. The other half received only lifestyle counseling and medication, including drugs to lower cholesterol, relax blood vessels, slow heart rate, and prevent blood clots. Both groups fared equally well after an average of 4 1/2 years, according to the study, also published online yesterday in The New England Journal of Medicine.
Stent manufacturer Boston Scientific Corp. of Natick criticized the study yesterday as not breaking any new ground, and said stents improve quality of life for patients with clogged arteries. The authors said their research suggested that improvements in quality of life were not statistically significant over the course of the study.
The use of angioplasty to open clogged arteries has taken off since the mid-1990s, increasing from about 430,000 procedures in 1995 to nearly 1.3 million in 2004 , with many of the more recent surgeries being done proactively, rather than after a life-threatening event.
The popularity of angioplasty has spurred debate among cardiologists, some of whom think the procedure is overused.
Dr. William Boden of Buffalo General Hospital said he designed the new study to determine how much added benefit angioplasty provided for people with few symptoms and was surprised to discover that, statistically, there was none.
The good news for patients, he said in a news conference: "You are no more or less at risk of developing a heart attack or dying if you defer angioplasty until some time down the road."
Angioplasty did provide a better quality of life than drugs alone for patients experiencing angina, the discomfort or chest pain that occurs when the heart muscle is deprived of oxygen.
Nissen said that angioplasty remains the treatment of choice for patients with a fully blocked artery, and that campaigns are underway to make sure patients having heart attacks are taken to hospitals that can swiftly perform an angioplasty.
Nissen and others said they think the procedure is probably done more often than needed, though the study's authors said they did not want to speculate about the amount of overuse.
Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center, said the bottom line is that patients and doctors need to make sure they're using angioplasty for the right reasons.
"To place a stent to reduce the chances of a heart attack or to prevent someone from dying, those are not reasons to put in a stent," said Maisel, chairman of a federal panel that examined stent safety.
Boston doctors tend toward the conservative, so they probably use the procedure less often than doctors elsewhere, according to Dr. Frederic S. Resnic, director of the cardiac catheterization laboratory at Brigham and Women's Hospital. Roughly 30 percent of the Brigham patients who get angioplasty have heart disease but are not in immediate danger of having a heart attack, he said.
"We have always been very careful to have detailed discussions with our patients with stable coronary artery disease, to make sure that they are comfortable and understand that we are considering the procedure to relieve the symptoms of angina, and reduce the number and amount of medications needed," he said.
The team of researchers, which included several from Hartford Hospital and the VA Connecticut Healthcare System, said their study may offer fresh evidence that heart disease is more of a systemwide than a localized problem in the body.
Using a stent addresses just one problem spot, but fails to correct other potentially more dangerous fat deposits in the diseased arteries.
The study, known as COURAGE, was paid for by the US Department of Veterans Affairs and the Canadian Institutes of Health Research , as well as 11 pharmaceutical companies, including Pfizer Inc., the maker of the world's top-selling drug, the cholesterol-lowering pill Lipitor .
The researchers acknowledge that one significant limitation of their study was that 85 percent of the patients were men and only 14 percent were non white.
Boston Scientific, which makes drug-coated stents, was sharply critical of the study.
"The results of the COURAGE trial don't really tell us much we didn't already know about the relative benefits of stents over drug therapy in the treatment of cardiovascular disease," the company said in a statement. "Stents have improved the lives of millions of patients, as amply demonstrated by a broad range of clinical trials and real-world experiences, but their benefits are found in safe, durable, and minimally-invasive relief of angina, rather than in further improving the already good survival of stable angina patients on medical therapy."
The company also criticized the study for failing to include drug-coated stents, which were not on the market when the study began.
Boden said that because drug-coated stents have not been shown to improve lifespan, using them instead of bare-metal stents would not have changed the study's results.
The research comes on the heels of a growing debate over whether some patients are getting unnecessary angioplasty, a procedure that involves using a tiny balloon and metal scaffolds called stents to prop open clogged arteries.
Angioplasty is recommended for those with fully blocked arteries or who have had a heart attack. But the new study, presented at the American College of Cardiology's annual meeting in New Orleans yesterday, should give doctors and their patients with partially obstructed arteries the confidence to put off angioplasty or to skip surgery altogether, according to the researchers.
"The results are very striking," said Dr. Steven Nissen , president of the American College of Cardiology, who was not involved in the study. "This is important for patients because it does now mean patients have choices. If your symptoms aren't so severe and aren't interfering with your lifestyle, you can afford to wait."
Half of the 2,300 patients studied underwent angioplasty and took heart drugs, and were told to make lifestyle changes, such as exercising, losing weight, and giving up smoking. The other half received only lifestyle counseling and medication, including drugs to lower cholesterol, relax blood vessels, slow heart rate, and prevent blood clots. Both groups fared equally well after an average of 4 1/2 years, according to the study, also published online yesterday in The New England Journal of Medicine.
Stent manufacturer Boston Scientific Corp. of Natick criticized the study yesterday as not breaking any new ground, and said stents improve quality of life for patients with clogged arteries. The authors said their research suggested that improvements in quality of life were not statistically significant over the course of the study.
The use of angioplasty to open clogged arteries has taken off since the mid-1990s, increasing from about 430,000 procedures in 1995 to nearly 1.3 million in 2004 , with many of the more recent surgeries being done proactively, rather than after a life-threatening event.
The popularity of angioplasty has spurred debate among cardiologists, some of whom think the procedure is overused.
Dr. William Boden of Buffalo General Hospital said he designed the new study to determine how much added benefit angioplasty provided for people with few symptoms and was surprised to discover that, statistically, there was none.
The good news for patients, he said in a news conference: "You are no more or less at risk of developing a heart attack or dying if you defer angioplasty until some time down the road."
Angioplasty did provide a better quality of life than drugs alone for patients experiencing angina, the discomfort or chest pain that occurs when the heart muscle is deprived of oxygen.
Nissen said that angioplasty remains the treatment of choice for patients with a fully blocked artery, and that campaigns are underway to make sure patients having heart attacks are taken to hospitals that can swiftly perform an angioplasty.
Nissen and others said they think the procedure is probably done more often than needed, though the study's authors said they did not want to speculate about the amount of overuse.
Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center, said the bottom line is that patients and doctors need to make sure they're using angioplasty for the right reasons.
"To place a stent to reduce the chances of a heart attack or to prevent someone from dying, those are not reasons to put in a stent," said Maisel, chairman of a federal panel that examined stent safety.
Boston doctors tend toward the conservative, so they probably use the procedure less often than doctors elsewhere, according to Dr. Frederic S. Resnic, director of the cardiac catheterization laboratory at Brigham and Women's Hospital. Roughly 30 percent of the Brigham patients who get angioplasty have heart disease but are not in immediate danger of having a heart attack, he said.
"We have always been very careful to have detailed discussions with our patients with stable coronary artery disease, to make sure that they are comfortable and understand that we are considering the procedure to relieve the symptoms of angina, and reduce the number and amount of medications needed," he said.
The team of researchers, which included several from Hartford Hospital and the VA Connecticut Healthcare System, said their study may offer fresh evidence that heart disease is more of a systemwide than a localized problem in the body.
Using a stent addresses just one problem spot, but fails to correct other potentially more dangerous fat deposits in the diseased arteries.
The study, known as COURAGE, was paid for by the US Department of Veterans Affairs and the Canadian Institutes of Health Research , as well as 11 pharmaceutical companies, including Pfizer Inc., the maker of the world's top-selling drug, the cholesterol-lowering pill Lipitor .
The researchers acknowledge that one significant limitation of their study was that 85 percent of the patients were men and only 14 percent were non white.
Boston Scientific, which makes drug-coated stents, was sharply critical of the study.
"The results of the COURAGE trial don't really tell us much we didn't already know about the relative benefits of stents over drug therapy in the treatment of cardiovascular disease," the company said in a statement. "Stents have improved the lives of millions of patients, as amply demonstrated by a broad range of clinical trials and real-world experiences, but their benefits are found in safe, durable, and minimally-invasive relief of angina, rather than in further improving the already good survival of stable angina patients on medical therapy."
The company also criticized the study for failing to include drug-coated stents, which were not on the market when the study began.
Boden said that because drug-coated stents have not been shown to improve lifespan, using them instead of bare-metal stents would not have changed the study's results.
Monday, March 26, 2007
Heart Stents No Better Than Treating Stable Heart Patients With Medication, Study Shows
The study of more than 2,000 patients found that those who underwent the expensive procedure, known as angioplasty, in non-emergency situations were no less likely to suffer a heart attack or die than those who only took aspirin and other medicines to thin their blood and lower blood pressure and cholesterol, along with adopting life style changes.
The study is the first large, well-designed comparison of angioplasty to non-surgical care for patients who are not actually having heart attack or in imminent danger of one. Patients routinely undergo the procedure to relieve chest pain and to reduce the risk of having or dying from a heart attack.
"The data are compelling," said William E. Boden of the University of Buffalo, whose findings were released Monday by The New England Journal of Medicine to coincide with a presentation at a meeting of the American College of Cardiology in New Orleans. "We do too many of these procedures."
Several experts said they expected the findings will prompt a major shift in how doctors treat thousands of patients suffering from heart disease -- the nation's leading cause of death.
"These findings are pretty explosive," said Steven Nissen, president of the American College of Cardiology. "I think this is going to shake things up pretty significantly."
The findings underscore the danger of rushing to adopt a procedure before careful studies have been conducted to fully determine its benefits, Boden and others said.
"There was just this intuitive belief that it would be beneficial," Boden said. "But no one had ever done a proper randomized trial to see whether it actually improved outcomes. In the meantime, a whole industry has been created around this."
The researchers and others stressed that angioplasty clearly benefits patients who are in the throes of a heart attack or are at very high risk for one. But the findings indicate that for a patient whose condition is stable, medical therapy is just as effective at reducing the major risks. Such patients constitute at least one-third of those undergoing the 1.2 million angioplasties performed each year, and perhaps as much as 85 percent.
Some cardiologists who specialize in the procedures, however, argued that the study did not focus on the sickest patients who are most likely to benefit and that the main purpose of angioplasty in many is to alleviate chest pain, not to prevent heart attacks.
"I don't think this is going to cause any huge paradigm shift," said Gregory J. Dehmer, president of the Society for Cardiovascular Angiography and Interventions. "This study was limited to a fairly select group of patients with very stable symptoms."
But Boden said the study did include patients with moderate to severe heart disease, and that many such patients undergo the procedure in the belief it will protect them against heart attacks.
In the procedure, doctors thread a tiny balloon into clogged arteries, inflate the balloon to clear the blockage and insert a stent -- a tiny wire lattice strut that props the artery open. The procedures cost at least $40,000 and are considered safe, although they do carry some risks.
The findings come on the heels of questions about the safety of a new generation of stents coated with drugs to keep arteries from reclosing. Those concerns had already led doctors curtail their use of the newer devices, and the new findings are expected to have a similar effect on angioplasty overall.
"There was an over-exuberance," said William O'Neill, a prominent cardiologist at the University of Miami. "I think we're getting a mid-course correction."
The findings could also help fuel a resurgence of bypass surgery, which has become far less common with the rise of angioplasty.
"There was this sense that angioplasty would produce the same result as bypass surgery," Nissen said. "I think this will cause a tilt toward more patients with stable conditions choosing medical therapy and more people who have more severe disease getting bypass surgery, which both relieves symptoms and reduces the risk for heart attack and death."
The new study involved 2,287 patients at 50 centers in the United States and Canada who had chest pain or other symptoms because one or more major arteries supplying blood to the heart had clogged. Half the patients received only standard medical treatment involving medication and life style changes such as quitting smoking, eating better and exercising. The other half received the same treatment plus angioplasty.
After about five years, the number of patients who experienced a heart attack, were hospitalized or died because of their heart problems was virtually identical in the two groups, the researchers found.
"There was no significant difference," Boden said. "The data are clear."
Although about one-third of patients who initially got medical treatment only later turned to angioplasty, the findings show how much medical treatment of heart disease has improved, Boden said.
"The paradigm for the last 20 years for patients like this been, 'Mr. Jones, you need a procedure.' End of discussion," Boden said. "I hope this will make people realize that patients have more options. They can safely choose to try medical therapy first."
Although study patients receiving angioplasty were somewhat more likely to be free of chest pain, known as angina, even that benefit was marginal, Boden said. After nearly five years, 74 percent of those patients were free of chest pain, compared to 72 percent of those who had medical treatment alone.
"One of the unexpected findings is that it's amazing how remarkably good medical therapy was for relieving angina," Boden said.
The study is the first large, well-designed comparison of angioplasty to non-surgical care for patients who are not actually having heart attack or in imminent danger of one. Patients routinely undergo the procedure to relieve chest pain and to reduce the risk of having or dying from a heart attack.
"The data are compelling," said William E. Boden of the University of Buffalo, whose findings were released Monday by The New England Journal of Medicine to coincide with a presentation at a meeting of the American College of Cardiology in New Orleans. "We do too many of these procedures."
Several experts said they expected the findings will prompt a major shift in how doctors treat thousands of patients suffering from heart disease -- the nation's leading cause of death.
"These findings are pretty explosive," said Steven Nissen, president of the American College of Cardiology. "I think this is going to shake things up pretty significantly."
The findings underscore the danger of rushing to adopt a procedure before careful studies have been conducted to fully determine its benefits, Boden and others said.
"There was just this intuitive belief that it would be beneficial," Boden said. "But no one had ever done a proper randomized trial to see whether it actually improved outcomes. In the meantime, a whole industry has been created around this."
The researchers and others stressed that angioplasty clearly benefits patients who are in the throes of a heart attack or are at very high risk for one. But the findings indicate that for a patient whose condition is stable, medical therapy is just as effective at reducing the major risks. Such patients constitute at least one-third of those undergoing the 1.2 million angioplasties performed each year, and perhaps as much as 85 percent.
Some cardiologists who specialize in the procedures, however, argued that the study did not focus on the sickest patients who are most likely to benefit and that the main purpose of angioplasty in many is to alleviate chest pain, not to prevent heart attacks.
"I don't think this is going to cause any huge paradigm shift," said Gregory J. Dehmer, president of the Society for Cardiovascular Angiography and Interventions. "This study was limited to a fairly select group of patients with very stable symptoms."
But Boden said the study did include patients with moderate to severe heart disease, and that many such patients undergo the procedure in the belief it will protect them against heart attacks.
In the procedure, doctors thread a tiny balloon into clogged arteries, inflate the balloon to clear the blockage and insert a stent -- a tiny wire lattice strut that props the artery open. The procedures cost at least $40,000 and are considered safe, although they do carry some risks.
The findings come on the heels of questions about the safety of a new generation of stents coated with drugs to keep arteries from reclosing. Those concerns had already led doctors curtail their use of the newer devices, and the new findings are expected to have a similar effect on angioplasty overall.
"There was an over-exuberance," said William O'Neill, a prominent cardiologist at the University of Miami. "I think we're getting a mid-course correction."
The findings could also help fuel a resurgence of bypass surgery, which has become far less common with the rise of angioplasty.
"There was this sense that angioplasty would produce the same result as bypass surgery," Nissen said. "I think this will cause a tilt toward more patients with stable conditions choosing medical therapy and more people who have more severe disease getting bypass surgery, which both relieves symptoms and reduces the risk for heart attack and death."
The new study involved 2,287 patients at 50 centers in the United States and Canada who had chest pain or other symptoms because one or more major arteries supplying blood to the heart had clogged. Half the patients received only standard medical treatment involving medication and life style changes such as quitting smoking, eating better and exercising. The other half received the same treatment plus angioplasty.
After about five years, the number of patients who experienced a heart attack, were hospitalized or died because of their heart problems was virtually identical in the two groups, the researchers found.
"There was no significant difference," Boden said. "The data are clear."
Although about one-third of patients who initially got medical treatment only later turned to angioplasty, the findings show how much medical treatment of heart disease has improved, Boden said.
"The paradigm for the last 20 years for patients like this been, 'Mr. Jones, you need a procedure.' End of discussion," Boden said. "I hope this will make people realize that patients have more options. They can safely choose to try medical therapy first."
Although study patients receiving angioplasty were somewhat more likely to be free of chest pain, known as angina, even that benefit was marginal, Boden said. After nearly five years, 74 percent of those patients were free of chest pain, compared to 72 percent of those who had medical treatment alone.
"One of the unexpected findings is that it's amazing how remarkably good medical therapy was for relieving angina," Boden said.
Heart stent makers brace for new heart study
Wall Street analysts and many doctors expect another potential setback for makers of stents when results of a blockbuster study Tuesday will answer whether an artery-opening procedure plus drugs is better than medication alone for lower-risk heart patients with chest pain.
It's the first big study to directly compare angioplasty procedures with drug therapy alone as a way to prevent heart attacks and deaths in non-emergency cases.
If the research reaches the conclusion many analysts and doctors expect — that angioplasty offers little or no lifesaving benefit over drugs for these patients — the finding would be the latest dose of bad news for makers of stents. The tiny mesh scaffolds are used in most angioplasties to keep vessels open after blockages have been cleared.
After new-model drug-coated stents reached the market in 2003, the global stent market including older bare-metal stents grew from about $2 billion a year to about $6 billion in 2005.
Drug-coated stents have been implanted in more than 6 million people worldwide a modern record for fastest use of a new medical device.
But use has fallen since new evidence emerged that drug-coated stents carry a slightly higher risk of triggering blood clots months or years later. Many doctors have returned to using the older bare-metal stents or doing bypass surgery instead of angioplasty until more is known.
The drug-coated stent market shrank last year and is expected to erode at a faster rate this year, due in part to anticipation of the newest heart study.
"This market went from zero to 100 mph, and now it's braking," said Citigroup analyst Matthew Dodds, who forecasts an 8 percent decline in overall stent sales this year, and slower market erosion through 2011.
For drug-coated stent makers such as Natick, Mass.-based Boston Scientific Corp. and New Brunswick, N.J.-based Johnson & Johnson, the shift has been costly, since drug-coated models cost around $2,100 apiece compared with $850 for bare-metal versions introduced more than a decade ago.
A stent is typically inserted into a heart artery during angioplasty, a procedure in which a miniature balloon is guided through a vessel in the groin and then inflated to flatten a clog and restore blood flow to the heart.
The stent keeps the artery open, and drug-coated ones ooze medication to keep scar tissue from forming and the vessel from squeezing shut again.
Angioplasty, with a cost ranging from about $10,000 to $38,000, is the top treatment for people suffering heart attacks. But as many as 85 percent of angioplasties are non-emergency and done for people with less severe blockages that cause recurrent chest pain.
The big study to be reported on Tuesday compared angioplasty plus optimal heart medications aspirin, beta blockers, ACE inhibitors and statins to lower cholesterol to medications alone. Results are to be presented Tuesday at the American College of Cardiology's annual meeting in New Orleans.
Pointing to earlier smaller studies, industry analysts and doctors believe angioplasties will be on the losing end.
"There's absolutely no indication" the study will show angioplasty is superior, said Thom Gunderson, an industry analyst with Piper Jaffray.
Dr. John Lopez, a cardiologist at the University of Chicago Hospitals, noted that the new study followed only patients whose heart conditions were stable, rather than those facing imminent risks. He believes that it's primarily higher-risk patients who benefit more from the artery-opening procedure.
"I'd be very surprised if there was a reduction in mortality," said Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center in Boston. "I suspect the bottom line we will be left with is that both options (angioplasty versus drugs only) are reasonable."
That result would mirror findings in recent studies including two within the past month that examined smaller groups.
If patients can't expect a better chance of long-term survival, angioplasty's cost may loom larger when it's elective, said Dr. David Cohen of St. Luke's Mid America Heart Institute in Kansas City, Mo.
Cohen said patients with stable heart problems, like the ones in the latest study, "probably should not be receiving this therapy (angioplasty) on a first-line basis."
Dr. Donald Baim, Boston Scientific's chief medical officer, said doctors should look beyond survival rates and consider whether angioplasty with stents relieves chest pain.
"The decision should be driven by the desire to limit chest pain with the least invasive alternative that's practical," Baim said.
Drug-coated stents accounted for about 89 percent of all stents implanted early last year, according to a study by Millennium Research Group, a Toronto-based firm that surveys doctors.
But that proportion fell to just 70 percent in February after more doctors opted for bare-metal versions because of the blood-clot fears from the drug-coated models.
Boston Scientific's drug-coated Taxus stent accounted for about 25 percent of the company's $2.1 billion in fourth-quarter sales — down from 40 percent before the company bought Guidant Corp. for $27 billion last spring to diversify a medical devices portfolio overly dependent on Taxus.
In comparison, J&J is a far bigger company with revenue of $13.7 billion last quarter and far less dependent on its drug-coated Cypher stent, which nevertheless has been a key driver of J&J's profits in recent years.
In addition to hurting Boston Scientific and Johnson & Johnson, the shift away from drug-coated stents could also hit companies with next-generation drug-coated models that are just hitting European markets and are soon expected to arrive in the U.S. Such companies include North Chicago, Ill.-based Abbott Laboratories Inc., and Minnesota-based Medtronic Inc. and St. Jude Medical Inc.
Piper Jaffray's Gunderson foresees further damage if Tuesday's research results are as expected.
"No matter how well anticipated these results are, and no matter how the stock prices have adjusted to factor in the results we're all anticipating, there is still that impact from the headlines in the morning," he said.
It's the first big study to directly compare angioplasty procedures with drug therapy alone as a way to prevent heart attacks and deaths in non-emergency cases.
If the research reaches the conclusion many analysts and doctors expect — that angioplasty offers little or no lifesaving benefit over drugs for these patients — the finding would be the latest dose of bad news for makers of stents. The tiny mesh scaffolds are used in most angioplasties to keep vessels open after blockages have been cleared.
After new-model drug-coated stents reached the market in 2003, the global stent market including older bare-metal stents grew from about $2 billion a year to about $6 billion in 2005.
Drug-coated stents have been implanted in more than 6 million people worldwide a modern record for fastest use of a new medical device.
But use has fallen since new evidence emerged that drug-coated stents carry a slightly higher risk of triggering blood clots months or years later. Many doctors have returned to using the older bare-metal stents or doing bypass surgery instead of angioplasty until more is known.
The drug-coated stent market shrank last year and is expected to erode at a faster rate this year, due in part to anticipation of the newest heart study.
"This market went from zero to 100 mph, and now it's braking," said Citigroup analyst Matthew Dodds, who forecasts an 8 percent decline in overall stent sales this year, and slower market erosion through 2011.
For drug-coated stent makers such as Natick, Mass.-based Boston Scientific Corp. and New Brunswick, N.J.-based Johnson & Johnson, the shift has been costly, since drug-coated models cost around $2,100 apiece compared with $850 for bare-metal versions introduced more than a decade ago.
A stent is typically inserted into a heart artery during angioplasty, a procedure in which a miniature balloon is guided through a vessel in the groin and then inflated to flatten a clog and restore blood flow to the heart.
The stent keeps the artery open, and drug-coated ones ooze medication to keep scar tissue from forming and the vessel from squeezing shut again.
Angioplasty, with a cost ranging from about $10,000 to $38,000, is the top treatment for people suffering heart attacks. But as many as 85 percent of angioplasties are non-emergency and done for people with less severe blockages that cause recurrent chest pain.
The big study to be reported on Tuesday compared angioplasty plus optimal heart medications aspirin, beta blockers, ACE inhibitors and statins to lower cholesterol to medications alone. Results are to be presented Tuesday at the American College of Cardiology's annual meeting in New Orleans.
Pointing to earlier smaller studies, industry analysts and doctors believe angioplasties will be on the losing end.
"There's absolutely no indication" the study will show angioplasty is superior, said Thom Gunderson, an industry analyst with Piper Jaffray.
Dr. John Lopez, a cardiologist at the University of Chicago Hospitals, noted that the new study followed only patients whose heart conditions were stable, rather than those facing imminent risks. He believes that it's primarily higher-risk patients who benefit more from the artery-opening procedure.
"I'd be very surprised if there was a reduction in mortality," said Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center in Boston. "I suspect the bottom line we will be left with is that both options (angioplasty versus drugs only) are reasonable."
That result would mirror findings in recent studies including two within the past month that examined smaller groups.
If patients can't expect a better chance of long-term survival, angioplasty's cost may loom larger when it's elective, said Dr. David Cohen of St. Luke's Mid America Heart Institute in Kansas City, Mo.
Cohen said patients with stable heart problems, like the ones in the latest study, "probably should not be receiving this therapy (angioplasty) on a first-line basis."
Dr. Donald Baim, Boston Scientific's chief medical officer, said doctors should look beyond survival rates and consider whether angioplasty with stents relieves chest pain.
"The decision should be driven by the desire to limit chest pain with the least invasive alternative that's practical," Baim said.
Drug-coated stents accounted for about 89 percent of all stents implanted early last year, according to a study by Millennium Research Group, a Toronto-based firm that surveys doctors.
But that proportion fell to just 70 percent in February after more doctors opted for bare-metal versions because of the blood-clot fears from the drug-coated models.
Boston Scientific's drug-coated Taxus stent accounted for about 25 percent of the company's $2.1 billion in fourth-quarter sales — down from 40 percent before the company bought Guidant Corp. for $27 billion last spring to diversify a medical devices portfolio overly dependent on Taxus.
In comparison, J&J is a far bigger company with revenue of $13.7 billion last quarter and far less dependent on its drug-coated Cypher stent, which nevertheless has been a key driver of J&J's profits in recent years.
In addition to hurting Boston Scientific and Johnson & Johnson, the shift away from drug-coated stents could also hit companies with next-generation drug-coated models that are just hitting European markets and are soon expected to arrive in the U.S. Such companies include North Chicago, Ill.-based Abbott Laboratories Inc., and Minnesota-based Medtronic Inc. and St. Jude Medical Inc.
Piper Jaffray's Gunderson foresees further damage if Tuesday's research results are as expected.
"No matter how well anticipated these results are, and no matter how the stock prices have adjusted to factor in the results we're all anticipating, there is still that impact from the headlines in the morning," he said.
Analysis: Stents' heart value in doubt
Doctors said Monday that angioplasty plus stenting a common, expensive heart procedure plus the best medical treatment failed to reduce the risk of death or heart attacks, when compared to optimal medical treatment alone.
In the blockbuster COURAGE Trial, doctors at the 56th annual scientific sessions of the American College of Cardiology said that the $38,000 angioplasty-plus-stent heart surgery now done a million times a year in the United States with the goal of freeing patients from chest pain did not, in the long run, even result in less pain.
"There are hundreds of thousands of Americans who are currently getting stents placed who do not need it as initial therapy," Dr. Raymond Gibbons, professor of medicine at the Mayo Medical School in Rochester, Minn., and president of the American Heart Association, told United Press International.
Thomas Ryan, senior consultant and emeritus chief of cardiology at Boston University, agreed.
"This study shows that, if you treat people vigorously and coach them and they get their blood pressure under control, patients can do just as well on medical therapy," he told UPI. But, he cautioned, "They can't just take a pill. This is hard work. They have to get out and exercise. They have to get maximum doses of lipid lowering drugs," he said.
Originally scheduled for simultaneous release at the ACC meeting and in the New England Journal of Medicine on Tuesday, the organizations reported the findings Monday after major portions of the report were leaked and were published online in various publications.
"Our findings parallel those reported in recent trials," said William Boden, chief of cardiology at Buffalo General and Millard Fillmore Hospitals. "In the aggregate, these studies, including our own, include outcome data on more than 5,000 patients and show that percutaneous coronary intervention angioplasty plus stenting has no effect in reducing major cardiovascular events."
Mayo's Gibbons said that the procedure does relieve pain in patients with angina, or chest pain, and still is the treatment of choice in people who have uncontrolled angina, a condition marked by pain even when at rest that is not well-controlled by use of drugs such as nitroglycerine.
Angioplasty with stent implantation is also recommended to open up coronary arteries in people in the throes of an acute heart attack. Such procedures can be lifesaving in these patients, he said.
In the COURAGE study, Boden, also professor of medicine and public health at the University at Buffalo School of Medicine and Biomedical Sciences, and colleagues across the United States and Canada recruited 2,287 patients who had evidence of heart disease.
Between 1999 and 2004, the researchers randomly assigned 1,149 patients to undergo angioplasty-plus-stent and to receive optimal medical therapy and 1,138 to receive optimal medical therapy alone.
The primary outcome of the study was the composite of death from any cause and nonfatal heart attacks. There were 211 such cases in the patients who received angioplasty and 202 patients in the medical-therapy-only patients. After about 4.6 years, about 19 percent of the patients who received angioplasty as an initial treatment experienced that primary outcome, compared with 18.5 percent of the medical treatment group a difference that did not reach statistical significance.
Similarly, regarding rates of heart attack, stroke or death the trial's secondary endpoint patients who got drugs and stents experienced these events at a rate of 20 percent, versus 19.5 percent in the drugs-alone group.
Boden, speaking at a press briefing Monday, said that one of the surprising findings of the study was that by five years, there was little difference between the groups among patients who were angina-free 74 percent of those having angioplasty and 72 percent of those following medical therapy.
"We set this study up with a hypothesis that angioplasty plus medical treatment would prove superior than just medical therapy alone," he said. "We wanted to give stenting the best chance to prove it had more benefits."
In angioplasty, doctors make a small incision in a patient's leg, allowing access to the main artery in the leg. Into that artery a balloon-tipped catheter is inserted. Using X-ray guidance, the catheter is advanced through the arterial system until it reaches the coronary arteries. When these arteries become blocked they can cause chest pain or heart attacks. The catheter is positioned at the point of coronary artery blockage and the balloon is inflated, crushing the blockage against the walls of the artery and opening the blood vessel.
To make sure blood keeps flowing, doctors then implant tiny mesh coils known as stents to act as scaffolding that props open the blood vessel.
Despite Monday's news, doctors were quick to note that stents still have a place in cardiac care.
"We shouldn't lose sight of the fact that revascularization angioplasty can be beneficial in acute situations," said Sidney Smith, professor of medicine at the University of North Carolina. "However, the foundation for all our work should be comprehensive medical therapy. If you get patients to take their medicine and treat to prescribed levels, patients can have benefits."
Jim Dove of Springfield, Ill., president-elect of the ACC, promised that the organization will consider sanctions against those individuals who were responsible for breaking the embargo on release of the study.
Steve Nissen, director of cardiovascular medicine at the Cleveland Clinic, and current ACC president, told UPI, "We are discussing sanctions. We will do what we think is right, but we will not do it rashly. We consider the embargo process an important part of the integrity of our studies."
In the blockbuster COURAGE Trial, doctors at the 56th annual scientific sessions of the American College of Cardiology said that the $38,000 angioplasty-plus-stent heart surgery now done a million times a year in the United States with the goal of freeing patients from chest pain did not, in the long run, even result in less pain.
"There are hundreds of thousands of Americans who are currently getting stents placed who do not need it as initial therapy," Dr. Raymond Gibbons, professor of medicine at the Mayo Medical School in Rochester, Minn., and president of the American Heart Association, told United Press International.
Thomas Ryan, senior consultant and emeritus chief of cardiology at Boston University, agreed.
"This study shows that, if you treat people vigorously and coach them and they get their blood pressure under control, patients can do just as well on medical therapy," he told UPI. But, he cautioned, "They can't just take a pill. This is hard work. They have to get out and exercise. They have to get maximum doses of lipid lowering drugs," he said.
Originally scheduled for simultaneous release at the ACC meeting and in the New England Journal of Medicine on Tuesday, the organizations reported the findings Monday after major portions of the report were leaked and were published online in various publications.
"Our findings parallel those reported in recent trials," said William Boden, chief of cardiology at Buffalo General and Millard Fillmore Hospitals. "In the aggregate, these studies, including our own, include outcome data on more than 5,000 patients and show that percutaneous coronary intervention angioplasty plus stenting has no effect in reducing major cardiovascular events."
Mayo's Gibbons said that the procedure does relieve pain in patients with angina, or chest pain, and still is the treatment of choice in people who have uncontrolled angina, a condition marked by pain even when at rest that is not well-controlled by use of drugs such as nitroglycerine.
Angioplasty with stent implantation is also recommended to open up coronary arteries in people in the throes of an acute heart attack. Such procedures can be lifesaving in these patients, he said.
In the COURAGE study, Boden, also professor of medicine and public health at the University at Buffalo School of Medicine and Biomedical Sciences, and colleagues across the United States and Canada recruited 2,287 patients who had evidence of heart disease.
Between 1999 and 2004, the researchers randomly assigned 1,149 patients to undergo angioplasty-plus-stent and to receive optimal medical therapy and 1,138 to receive optimal medical therapy alone.
The primary outcome of the study was the composite of death from any cause and nonfatal heart attacks. There were 211 such cases in the patients who received angioplasty and 202 patients in the medical-therapy-only patients. After about 4.6 years, about 19 percent of the patients who received angioplasty as an initial treatment experienced that primary outcome, compared with 18.5 percent of the medical treatment group a difference that did not reach statistical significance.
Similarly, regarding rates of heart attack, stroke or death the trial's secondary endpoint patients who got drugs and stents experienced these events at a rate of 20 percent, versus 19.5 percent in the drugs-alone group.
Boden, speaking at a press briefing Monday, said that one of the surprising findings of the study was that by five years, there was little difference between the groups among patients who were angina-free 74 percent of those having angioplasty and 72 percent of those following medical therapy.
"We set this study up with a hypothesis that angioplasty plus medical treatment would prove superior than just medical therapy alone," he said. "We wanted to give stenting the best chance to prove it had more benefits."
In angioplasty, doctors make a small incision in a patient's leg, allowing access to the main artery in the leg. Into that artery a balloon-tipped catheter is inserted. Using X-ray guidance, the catheter is advanced through the arterial system until it reaches the coronary arteries. When these arteries become blocked they can cause chest pain or heart attacks. The catheter is positioned at the point of coronary artery blockage and the balloon is inflated, crushing the blockage against the walls of the artery and opening the blood vessel.
To make sure blood keeps flowing, doctors then implant tiny mesh coils known as stents to act as scaffolding that props open the blood vessel.
Despite Monday's news, doctors were quick to note that stents still have a place in cardiac care.
"We shouldn't lose sight of the fact that revascularization angioplasty can be beneficial in acute situations," said Sidney Smith, professor of medicine at the University of North Carolina. "However, the foundation for all our work should be comprehensive medical therapy. If you get patients to take their medicine and treat to prescribed levels, patients can have benefits."
Jim Dove of Springfield, Ill., president-elect of the ACC, promised that the organization will consider sanctions against those individuals who were responsible for breaking the embargo on release of the study.
Steve Nissen, director of cardiovascular medicine at the Cleveland Clinic, and current ACC president, told UPI, "We are discussing sanctions. We will do what we think is right, but we will not do it rashly. We consider the embargo process an important part of the integrity of our studies."
Tuesday, March 6, 2007
House to scrutinize marketing of stents
As part of a federal inquiry into drug and medical-device marketing, Boston Scientific Corp. was asked by Congress last week to submit to investigators internal documents, marketing plans, and clinical data related to its top-selling product, the Taxus drug-coated stent.
In a letter sent to Boston Scientific chief executive Jim Tobin , Representative Henry Waxman , chairman of the chief investigative committee of the House of Representatives, requested information about whether the Natick company's marketing department funded any clinical studies on Taxus stents, whether it paid any of the studies' authors or doctors, and whether it withheld the results of any Taxus studies.
Waxman , a California Democrat, sent an identical letter to Cordis Corp. , the division of Johnson & Johnson that makes the only competing drug-coated stent in the United States. The letters cited "concerns about the safety and off-label use" of the stents, which were the subject of a two-day Food and Drug Administration hearing in December.
Both companies issued statements saying they planned to cooperate with Waxman's request.
Since their introduction in 2003, drug-coated coronary stents have become the fastest-selling medical device in history, bringing in about $5 billion a year for Boston Scientific and Johnson & Johnson, which is based in New Jersey. The tiny wire-mesh tubes are implanted to hold open cleared heart arteries.
The companies used powerful marketing campaigns to launch their products for use instead of an older generation of bare-metal stents. Recent data shows that while drug-coated stents can decrease the rate at which patients need to return for new heart procedures, they also slightly raise the risk of long-term clotting over the older, cheaper stents.
Waxman's letter cited the December FDA hearing, at which a panel of experts combed through a wide array of data on the benefits and risks of drug-coated stents. The panelists concluded that stents were safe and effective when used on the subset of heart patients for which they were initially approved, but they raised a flag of caution over the large number of patients who receive drug-coated stents despite falling outside those guidelines.
The letter came from the House Committee on Oversight and Government Reform, which Waxman chairs.
His request focuses on how the companies marketed their stents, asking for records of sales-training, presentations to doctors, and "all internal or external presentations or reports relating to off-label use." It also asks for a record of their funding of cardiology societies and events.
In a letter sent to Boston Scientific chief executive Jim Tobin , Representative Henry Waxman , chairman of the chief investigative committee of the House of Representatives, requested information about whether the Natick company's marketing department funded any clinical studies on Taxus stents, whether it paid any of the studies' authors or doctors, and whether it withheld the results of any Taxus studies.
Waxman , a California Democrat, sent an identical letter to Cordis Corp. , the division of Johnson & Johnson that makes the only competing drug-coated stent in the United States. The letters cited "concerns about the safety and off-label use" of the stents, which were the subject of a two-day Food and Drug Administration hearing in December.
Both companies issued statements saying they planned to cooperate with Waxman's request.
Since their introduction in 2003, drug-coated coronary stents have become the fastest-selling medical device in history, bringing in about $5 billion a year for Boston Scientific and Johnson & Johnson, which is based in New Jersey. The tiny wire-mesh tubes are implanted to hold open cleared heart arteries.
The companies used powerful marketing campaigns to launch their products for use instead of an older generation of bare-metal stents. Recent data shows that while drug-coated stents can decrease the rate at which patients need to return for new heart procedures, they also slightly raise the risk of long-term clotting over the older, cheaper stents.
Waxman's letter cited the December FDA hearing, at which a panel of experts combed through a wide array of data on the benefits and risks of drug-coated stents. The panelists concluded that stents were safe and effective when used on the subset of heart patients for which they were initially approved, but they raised a flag of caution over the large number of patients who receive drug-coated stents despite falling outside those guidelines.
The letter came from the House Committee on Oversight and Government Reform, which Waxman chairs.
His request focuses on how the companies marketed their stents, asking for records of sales-training, presentations to doctors, and "all internal or external presentations or reports relating to off-label use." It also asks for a record of their funding of cardiology societies and events.
Monday, February 26, 2007
Stent research alarms patients
John Wehr couldn't believe what was he was reading. An article on drug-coated stents, the kind used to prop open his two clogged coronary arteries last June, said the devices have a ''small but significantly increased risk'' of life-threatening side-effects.
Worried, the 78-year-old retired Bethlehem Steel Corp. accountant clipped the article and called his cardiologist. He wasn't alone.
Drug-coated stents tiny mesh tubes coated in chemotherapy drugs have been considered the best medicine had to offer, superior to the uncoated variety in their ability to keep scar tissue at bay and prevent coronary arteries from reclosing.
They've been inserted in 6 million heart patients nationwide, including 5,000 in the Lehigh Valley.
But heart specialists have been forced to reconsider their use since December, when new research showed they are more likely to cause blood clots than do the bare-metal variety and the clots can appear six months to years after the stents are placed.
Clotting is a natural reaction to injury, but studies conducted in the United States and Sweden found that blood clots were getting stuck inside the stents, cutting off blood flow and causing heart attacks and sudden death. Researchers put the risk of developing clots at about 1 in 200-500 people.
Area cardiologists said they've found blood clots in the drug-coated stents of patients who survived heart attacks. And they can only presume that some others have died from the complication as well. Without autopsies, they can't know for sure.
Rapid escalation of use of the devices has only added to the alarm. Since they went on the market four years ago, drug-coated stents have far surpassed bare metal, becoming the stent of choice in 80-90 percent of all cases.
''It's a huge amount,'' local cardiologist Bryan Kluck acknowledged. At Lehigh Valley Hospital-Cedar Crest, where Kluck practices, cardiologists inserted the devices in about 1,700 patients last year. Over the same time at St. Luke's Hospital-Fountain Hill, about 1,000 patients received one or more drug-coated stents. Another 500 or so received the devices at Easton Hospital in Wilson.
In response to the findings, the American Heart Association, American College of Cardiology and other medical groups in early January recommended that most patients with drug-coated stents remain on anti-clotting medicines, such as the prescription drug Plavix, and aspirin, for at least a year, possibly indefinitely.
Experts believe continued use of anti-clotting medicines is the best recourse because research shows that patients who stayed on the drugs for a year fared the best among those studied. The 3-5 percent increased risk of blood clots occurred primarily among patients who stopped taking the medicines after six months.
Patients were supposed to stay on the pills for one to six months, depending on the type of stent used. However, one study showed the average time patients took the blood-thinners was 45 days.
''The increased risk [of blood clots] is very small and likely to be overcome if patients stay on anti-clotting medicines,'' noted Dr. Deepak Bhatt, a cardiologist and researcher at the Cleveland Clinic, which analyzed 14 studies involving drug-coated stents.
Promising, but not perfect
Two brands of drug-coated stents are used in the United States: Taxus by Boston Scientific Corp. and Cypher by Johnson & Johnson's Cordis Corp.
Placed inside a blocked coronary artery on the end of a deflated balloon, the stents are locked in place when the balloon is inflated. They act as a buttress to keep fatty deposits pinned against the artery wall. They restore blood flow to patients in the throes of a heart attack or who have blockages.
When they first came on the market, the drug-coated stents were recommended only for patients at low risk, such as those with small blockages in single vessels. But because early results with such patients looked so good, doctors used them in more common and complicated cases and in sicker patients.
Doctors had hints of a clotting problem from earlier studies, but it wasn't until the release of more conclusive data in December, much of it produced by the Duke Clinical Research Institute in Durham, N.C., that concern reached a critical level.
A rare summit of international experts called days later by the U.S. Food and Drug Administration produced the recommendation that patients remain on anti-clotting medication for a year or more.
But Dr. Robert A. Harrington, a professor of medicine in the division of cardiology and director of Duke's Clinical Research Institute, said the recommendation puts doctors and patients in another predicament.
''Are we committing millions of patients to lifelong [anti-clotting medicine] with its attendant costs and risks?'' he asks in an editorial about the blood-clot problems in a December issue of the Journal of the American College of Cardiology.
Plavix generic name clopidogrel and other blood-thinners can cause life-threatening internal bleeding in some patients, such as those with ulcers. It also has been shown to be no better than low-cost aspirin at preventing a first heart attack.
The Cleveland Clinic's Bhatt, however, doesn't think the side-effects of blood thinners are reason enough not to continue using drug-coated stents.
''Everything has risks,'' he said.
Weighing the risks
Some patients were so upset by the research that they asked that the stents be removed something doctors generally don't do, considering it much riskier than leaving the mesh tubes in place.
Cardiologists hope they can quickly learn which patients, beyond the low-risk, are best suited to drug-coated stents from patient registries and continued research. Or that the next generation of stents won't cause blood clots. In the works are stents with different coatings and others made to dissolve over time.
Until they have more answers, local and national specialists are extending the use of anti-clotting medicine. They also are being more selective in using drug-coated stents, perhaps precluding patients with long blockages or blockages that extend beyond one artery, persons with diabetes, persons scheduled for lung or colon cancer surgery or persons who have trouble keeping up pill regimens.
''There was a time that I'd try any case I could to use drug-coated stents,'' said Dr. Gary Costacurta, chief of cardiology at Easton Hospital in Wilson.
Now, Costacurta said, he may use bare-metal stents for patients with long blockages or for patients with blood vessels that are large in diameter.
LVH's Kluck said being more selective may not be so easy especially in the emergency room.
About 20 percent of the patients who receive stents arrive in the ER with chest pains and signs of imminent danger to the heart. It's a scenario in which seconds can make a difference, he said, in how much damage occurs to the heart and whether or not the patient lives.
Such cases leave little time for a full patient history, Kluck said. What medicines the patient had been taking or stopped taking and whether they have had bleeding problems in the past might not be known. ''It's not clear if plain stents are better than drug-coated'' for such patients, he said. ''We must probe deeper to know.''
Dr. Peter Puleo, a cardiologist and medical director of the catheterization laboratory at St. Luke's Hospital in Fountain Hill, said he started telling his patients to stay on anti-clotting medicines for two years when he read early studies suggesting a problem.
Puleo said he uses bare-metal stents on patients with long blockages or larger blood vessels. He said he is less worried about patients bleeding from blood-thinners than he is about heart attack and death from blood clots. ''Death from internal bleeding is even more unusual than late-term thrombosis,'' Puleo said, using another term for blood clots. ''In cardiology, more people clot than bleed to death.''
''It makes people nervous about continuing [on the medicines], but you can get through it,'' Puleo said.
Dr. J. Patrick Kleaveland, medical director of the catheterization laboratory at LVH and co-director of the lab at Grand View Hospital in West Rockhill Township, Bucks County, said drug-coated stents are still safe and effective in reducing restenosis for patients with simple, straight-forward blockages.
Patients at higher risk may still benefit as well, Kleaveland said, if they can stay on anti-clotting medicines for at least a year without uncontrolled bleeding. ''The patients I've seen with the most devastating problems are those who stopped taking their medicines prematurely,'' he said.
Reasons patients stop taking anti-clotting medication range from not being able to afford the pills, which cost $3-$4 a piece, to not feeling well on them or having difficulty keeping up with the regimen.
But cardiologists warn that stopping, even for a few days, could prove fatal if the body throws blood clots at the braced vessels.
''The first sign of trouble could be the total blockage of a stent, artery and blood flow,'' Kluck said. In other words, a sudden, massive heart attack.
Lehigh County Judge Edward Reibman stopped taking his prescription blood-thinner months after receiving a drug-coated stent in 2005. He counts himself lucky he didn't develop blood clots.
''When I had the stent put in, I was prescribed Plavix and aspirin, but I felt lousy on them,'' Reibman said, remembering muscle and bone pain.
He stopped the Plavix, switched to another anti-clotting drug and after a few months stopped that, too. But he continued taking a baby aspirin a day.
At a checkup in December, when news broke of the risk of blood clots, Reibman's doctor told him to resume the Plavix.
The judge wonders what new risks will come with the prescription medicine, but said he isn't judging prior decisions.
''Everyone thought the stents were fine. No one knew about this late stent [blood-clotting] problem then,'' he said. ''You make decisions with the best information you have at the time, and as science develops, you learn more and hopefully make more decisions.''
Worried, the 78-year-old retired Bethlehem Steel Corp. accountant clipped the article and called his cardiologist. He wasn't alone.
Drug-coated stents tiny mesh tubes coated in chemotherapy drugs have been considered the best medicine had to offer, superior to the uncoated variety in their ability to keep scar tissue at bay and prevent coronary arteries from reclosing.
They've been inserted in 6 million heart patients nationwide, including 5,000 in the Lehigh Valley.
But heart specialists have been forced to reconsider their use since December, when new research showed they are more likely to cause blood clots than do the bare-metal variety and the clots can appear six months to years after the stents are placed.
Clotting is a natural reaction to injury, but studies conducted in the United States and Sweden found that blood clots were getting stuck inside the stents, cutting off blood flow and causing heart attacks and sudden death. Researchers put the risk of developing clots at about 1 in 200-500 people.
Area cardiologists said they've found blood clots in the drug-coated stents of patients who survived heart attacks. And they can only presume that some others have died from the complication as well. Without autopsies, they can't know for sure.
Rapid escalation of use of the devices has only added to the alarm. Since they went on the market four years ago, drug-coated stents have far surpassed bare metal, becoming the stent of choice in 80-90 percent of all cases.
''It's a huge amount,'' local cardiologist Bryan Kluck acknowledged. At Lehigh Valley Hospital-Cedar Crest, where Kluck practices, cardiologists inserted the devices in about 1,700 patients last year. Over the same time at St. Luke's Hospital-Fountain Hill, about 1,000 patients received one or more drug-coated stents. Another 500 or so received the devices at Easton Hospital in Wilson.
In response to the findings, the American Heart Association, American College of Cardiology and other medical groups in early January recommended that most patients with drug-coated stents remain on anti-clotting medicines, such as the prescription drug Plavix, and aspirin, for at least a year, possibly indefinitely.
Experts believe continued use of anti-clotting medicines is the best recourse because research shows that patients who stayed on the drugs for a year fared the best among those studied. The 3-5 percent increased risk of blood clots occurred primarily among patients who stopped taking the medicines after six months.
Patients were supposed to stay on the pills for one to six months, depending on the type of stent used. However, one study showed the average time patients took the blood-thinners was 45 days.
''The increased risk [of blood clots] is very small and likely to be overcome if patients stay on anti-clotting medicines,'' noted Dr. Deepak Bhatt, a cardiologist and researcher at the Cleveland Clinic, which analyzed 14 studies involving drug-coated stents.
Promising, but not perfect
Two brands of drug-coated stents are used in the United States: Taxus by Boston Scientific Corp. and Cypher by Johnson & Johnson's Cordis Corp.
Placed inside a blocked coronary artery on the end of a deflated balloon, the stents are locked in place when the balloon is inflated. They act as a buttress to keep fatty deposits pinned against the artery wall. They restore blood flow to patients in the throes of a heart attack or who have blockages.
When they first came on the market, the drug-coated stents were recommended only for patients at low risk, such as those with small blockages in single vessels. But because early results with such patients looked so good, doctors used them in more common and complicated cases and in sicker patients.
Doctors had hints of a clotting problem from earlier studies, but it wasn't until the release of more conclusive data in December, much of it produced by the Duke Clinical Research Institute in Durham, N.C., that concern reached a critical level.
A rare summit of international experts called days later by the U.S. Food and Drug Administration produced the recommendation that patients remain on anti-clotting medication for a year or more.
But Dr. Robert A. Harrington, a professor of medicine in the division of cardiology and director of Duke's Clinical Research Institute, said the recommendation puts doctors and patients in another predicament.
''Are we committing millions of patients to lifelong [anti-clotting medicine] with its attendant costs and risks?'' he asks in an editorial about the blood-clot problems in a December issue of the Journal of the American College of Cardiology.
Plavix generic name clopidogrel and other blood-thinners can cause life-threatening internal bleeding in some patients, such as those with ulcers. It also has been shown to be no better than low-cost aspirin at preventing a first heart attack.
The Cleveland Clinic's Bhatt, however, doesn't think the side-effects of blood thinners are reason enough not to continue using drug-coated stents.
''Everything has risks,'' he said.
Weighing the risks
Some patients were so upset by the research that they asked that the stents be removed something doctors generally don't do, considering it much riskier than leaving the mesh tubes in place.
Cardiologists hope they can quickly learn which patients, beyond the low-risk, are best suited to drug-coated stents from patient registries and continued research. Or that the next generation of stents won't cause blood clots. In the works are stents with different coatings and others made to dissolve over time.
Until they have more answers, local and national specialists are extending the use of anti-clotting medicine. They also are being more selective in using drug-coated stents, perhaps precluding patients with long blockages or blockages that extend beyond one artery, persons with diabetes, persons scheduled for lung or colon cancer surgery or persons who have trouble keeping up pill regimens.
''There was a time that I'd try any case I could to use drug-coated stents,'' said Dr. Gary Costacurta, chief of cardiology at Easton Hospital in Wilson.
Now, Costacurta said, he may use bare-metal stents for patients with long blockages or for patients with blood vessels that are large in diameter.
LVH's Kluck said being more selective may not be so easy especially in the emergency room.
About 20 percent of the patients who receive stents arrive in the ER with chest pains and signs of imminent danger to the heart. It's a scenario in which seconds can make a difference, he said, in how much damage occurs to the heart and whether or not the patient lives.
Such cases leave little time for a full patient history, Kluck said. What medicines the patient had been taking or stopped taking and whether they have had bleeding problems in the past might not be known. ''It's not clear if plain stents are better than drug-coated'' for such patients, he said. ''We must probe deeper to know.''
Dr. Peter Puleo, a cardiologist and medical director of the catheterization laboratory at St. Luke's Hospital in Fountain Hill, said he started telling his patients to stay on anti-clotting medicines for two years when he read early studies suggesting a problem.
Puleo said he uses bare-metal stents on patients with long blockages or larger blood vessels. He said he is less worried about patients bleeding from blood-thinners than he is about heart attack and death from blood clots. ''Death from internal bleeding is even more unusual than late-term thrombosis,'' Puleo said, using another term for blood clots. ''In cardiology, more people clot than bleed to death.''
''It makes people nervous about continuing [on the medicines], but you can get through it,'' Puleo said.
Dr. J. Patrick Kleaveland, medical director of the catheterization laboratory at LVH and co-director of the lab at Grand View Hospital in West Rockhill Township, Bucks County, said drug-coated stents are still safe and effective in reducing restenosis for patients with simple, straight-forward blockages.
Patients at higher risk may still benefit as well, Kleaveland said, if they can stay on anti-clotting medicines for at least a year without uncontrolled bleeding. ''The patients I've seen with the most devastating problems are those who stopped taking their medicines prematurely,'' he said.
Reasons patients stop taking anti-clotting medication range from not being able to afford the pills, which cost $3-$4 a piece, to not feeling well on them or having difficulty keeping up with the regimen.
But cardiologists warn that stopping, even for a few days, could prove fatal if the body throws blood clots at the braced vessels.
''The first sign of trouble could be the total blockage of a stent, artery and blood flow,'' Kluck said. In other words, a sudden, massive heart attack.
Lehigh County Judge Edward Reibman stopped taking his prescription blood-thinner months after receiving a drug-coated stent in 2005. He counts himself lucky he didn't develop blood clots.
''When I had the stent put in, I was prescribed Plavix and aspirin, but I felt lousy on them,'' Reibman said, remembering muscle and bone pain.
He stopped the Plavix, switched to another anti-clotting drug and after a few months stopped that, too. But he continued taking a baby aspirin a day.
At a checkup in December, when news broke of the risk of blood clots, Reibman's doctor told him to resume the Plavix.
The judge wonders what new risks will come with the prescription medicine, but said he isn't judging prior decisions.
''Everyone thought the stents were fine. No one knew about this late stent [blood-clotting] problem then,'' he said. ''You make decisions with the best information you have at the time, and as science develops, you learn more and hopefully make more decisions.''
Tuesday, February 13, 2007
What's Up With Stents, Docs?
It's not often that the New England Journal of Medicine devotes most of its editorial content to a single subject and releases the information early online. That's exactly what it did Monday with a series of five studies and several commentaries on drug-eluting coronary stents. As the editors explained, "Our motivation is the recent concern that the implantation of drug-eluting stents, as compared with bare-metal stents, may be associated with a small increased risk of late stent thrombosis, a potentially fatal complication."
Drug-eluting stents were hailed as a "breakthrough technology" in 2003 and 2004, when the FDA approved the Cypher and Taxus stents, respectively. Like the bare-metal stents that preceded them, these tiny wire-mesh scaffolds were designed to prop open narrowed blood vessels (a problem known as stenosis), reducing the chest pain known as angina. Unlike bare-metal stents, however, the Cypher and Taxus devices were coated with drugs, the purpose of which was to prevent arterial cells from multiplying rapidly and narrowing the blood vessels again, a process known as "restenosis."
Drug-eluting stents caught on rapidly. By the end of 2004, they were used in 80-90 percent of stenting procedures. (Several million have now been implanted worldwide.) But concerns about their safety began to surface in the fall of 2005 and came to a head in March 2006, when a large population study in Sweden suggested that, between 7 and 18 months after implantation, patients with drug-eluting stents had higher rates of so-called stent thrombosis, in which a blood clot forms on exposed metalheart attacks an event often associated with acute heart attacks and sudden death. (An animation illustrating both restenosis and stent thrombosis is available at www.nejm.org.) These concerns prompted the FDA to convene a panel of experts in December to sift through the available evidence.
The new studies give more detailed versions of the evidence presented at the FDA in December. Unfortunately, a clear conclusion is still not readily available. "You could write whatever headline you wanted," says Dr. William Maisel of Beth Israel Deaconess Medical Center in Boston, who chaired the FDA panel and wrote one of the overview papers in the journal. "You could write that drug-eluting stents and bare-metal stents are equally safe [the conclusion of a study headed by Christian Spaulding in France]. Or you could write that there was more stent thrombosis after a year with drug-eluting stents, but no significant differences in overall rates of death and heart attack at four years [the conclusion of another paper by Gregg Stone at Columbia University]." Or, frankly, you could write that there was not only more stent thrombosis after six months with drug-eluting stents, but also death rates 18 to 32 percent higher three years afterwards, as indicated in the Swedish study.
How could the papers reach such different conclusions? The formal studies that led to FDA approval longer, follow-up versions of which constitute four of the five studies in the New England Journal enrolled only patients with the simplest, least complicated cases of arterial stenosis. When the FDA granted approval for drug-eluting stents, it was for use in patients like these. But once the devices were approved, doctors started using them in patients with more complex problems, too, such as longer lesions and problems in multiple vessels. The Swedish registry included these "real-world" patients, not just the ideal candidates in the approval trials.
What's a prospective patient to do? If you're thinking about getting a stent, here are three points to consider:
First, almost everyone seems to agree that drug-eluting stents lead to a slightly greater risk of stent thrombosis six months or more after implantation of the device. That's not surprising. Because the arterial lining doesn't grow back as quickly as with bare-metal stents, the metal mesh is exposed for longer, presenting a rough surface on which clots can form. Even Dr. Donald Baim, chief medical and scientific officer of Boston Scientific, which makes the Taxus stent, agreed with the point in an audio interview posted on the New England Journal's Web site. To compensate for the increased risk, the FDA panel recommended that patients stay on blood-thinning agents like aspirin and Plavix for at least 12 months afterwards an increase from the previous recommendation of 3-6 months. In addition, recipients should not undergo elective surgery during that time.
Second, it's important to realize that stents are mainly effective for relief of angina. There's very little evidence that they prevent heart attacks or reduce deaths, except when implanted during a heart attack. That's because most heart attacks don't come from narrowed arteries, but from ruptured plaque, around which massive clots form. So if you suffer from angina and want an improved quality of life, stents are very likely to help. If it's a heart attack you're trying to prevent, then it's not clear how great the benefit may be. (In the long run, some doctors suggest that a better option for preventing heart attacks may be aggressive drug therapy for high cholesterol and blood pressure. It's logical that drugs might help more, since they affect the entire cardiovascular system, not just a single artery. We'll know better next month, when a large trial comparing stents-plus-drugs against drug therapy alone will be unveiled at the American College of Cardiology meeting.)
Third, says Maisel, despite the uncertainties, drug-eluting stents have been an important advance in the management of coronary artery disease. They clearly reduce the occurrence of restenosis and hence the need for repeat procedures. Patients with simple obstructions in coronary arteries the patients for whom the devices were approved will likely do well with them. "But there's no free lunch," he warns. Anti-clotting therapy is important. For patients with more complicated cases, the equation is still uncertain.
Drug-eluting stents were hailed as a "breakthrough technology" in 2003 and 2004, when the FDA approved the Cypher and Taxus stents, respectively. Like the bare-metal stents that preceded them, these tiny wire-mesh scaffolds were designed to prop open narrowed blood vessels (a problem known as stenosis), reducing the chest pain known as angina. Unlike bare-metal stents, however, the Cypher and Taxus devices were coated with drugs, the purpose of which was to prevent arterial cells from multiplying rapidly and narrowing the blood vessels again, a process known as "restenosis."
Drug-eluting stents caught on rapidly. By the end of 2004, they were used in 80-90 percent of stenting procedures. (Several million have now been implanted worldwide.) But concerns about their safety began to surface in the fall of 2005 and came to a head in March 2006, when a large population study in Sweden suggested that, between 7 and 18 months after implantation, patients with drug-eluting stents had higher rates of so-called stent thrombosis, in which a blood clot forms on exposed metalheart attacks an event often associated with acute heart attacks and sudden death. (An animation illustrating both restenosis and stent thrombosis is available at www.nejm.org.) These concerns prompted the FDA to convene a panel of experts in December to sift through the available evidence.
The new studies give more detailed versions of the evidence presented at the FDA in December. Unfortunately, a clear conclusion is still not readily available. "You could write whatever headline you wanted," says Dr. William Maisel of Beth Israel Deaconess Medical Center in Boston, who chaired the FDA panel and wrote one of the overview papers in the journal. "You could write that drug-eluting stents and bare-metal stents are equally safe [the conclusion of a study headed by Christian Spaulding in France]. Or you could write that there was more stent thrombosis after a year with drug-eluting stents, but no significant differences in overall rates of death and heart attack at four years [the conclusion of another paper by Gregg Stone at Columbia University]." Or, frankly, you could write that there was not only more stent thrombosis after six months with drug-eluting stents, but also death rates 18 to 32 percent higher three years afterwards, as indicated in the Swedish study.
How could the papers reach such different conclusions? The formal studies that led to FDA approval longer, follow-up versions of which constitute four of the five studies in the New England Journal enrolled only patients with the simplest, least complicated cases of arterial stenosis. When the FDA granted approval for drug-eluting stents, it was for use in patients like these. But once the devices were approved, doctors started using them in patients with more complex problems, too, such as longer lesions and problems in multiple vessels. The Swedish registry included these "real-world" patients, not just the ideal candidates in the approval trials.
What's a prospective patient to do? If you're thinking about getting a stent, here are three points to consider:
First, almost everyone seems to agree that drug-eluting stents lead to a slightly greater risk of stent thrombosis six months or more after implantation of the device. That's not surprising. Because the arterial lining doesn't grow back as quickly as with bare-metal stents, the metal mesh is exposed for longer, presenting a rough surface on which clots can form. Even Dr. Donald Baim, chief medical and scientific officer of Boston Scientific, which makes the Taxus stent, agreed with the point in an audio interview posted on the New England Journal's Web site. To compensate for the increased risk, the FDA panel recommended that patients stay on blood-thinning agents like aspirin and Plavix for at least 12 months afterwards an increase from the previous recommendation of 3-6 months. In addition, recipients should not undergo elective surgery during that time.
Second, it's important to realize that stents are mainly effective for relief of angina. There's very little evidence that they prevent heart attacks or reduce deaths, except when implanted during a heart attack. That's because most heart attacks don't come from narrowed arteries, but from ruptured plaque, around which massive clots form. So if you suffer from angina and want an improved quality of life, stents are very likely to help. If it's a heart attack you're trying to prevent, then it's not clear how great the benefit may be. (In the long run, some doctors suggest that a better option for preventing heart attacks may be aggressive drug therapy for high cholesterol and blood pressure. It's logical that drugs might help more, since they affect the entire cardiovascular system, not just a single artery. We'll know better next month, when a large trial comparing stents-plus-drugs against drug therapy alone will be unveiled at the American College of Cardiology meeting.)
Third, says Maisel, despite the uncertainties, drug-eluting stents have been an important advance in the management of coronary artery disease. They clearly reduce the occurrence of restenosis and hence the need for repeat procedures. Patients with simple obstructions in coronary arteries the patients for whom the devices were approved will likely do well with them. "But there's no free lunch," he warns. Anti-clotting therapy is important. For patients with more complicated cases, the equation is still uncertain.
Drug-coated stents don't cut risk of heart attacks
The most exhaustive studies yet published on drug-coated stents show that the widely used heart devices are no better at preventing heart attacks and death than the older, cheaper devices they replaced, and in some cases may be slightly worse.
Since their introduction in 2003, the tiny wire tubes, about the size of a pen spring, have become fastest-selling medical devices in history, used in millions of people worldwide. They have been a boon to Boston Scientific Corp. of Natick, the largest life-science company in Massachusetts and one of the world's two major stent manufacturers.
However, safety concerns have emerged in the past year because drug-coated stents appear to carry a higher long-term risk of blood clots forming in the arteries that nourish the heart.
A series of studies released today by the New England Journal of Medicine showed that drug-coated stents carried one clear benefit: patients who receive them are less likely to return to the hospital for a repeat heart-clearing procedure.
Viewed over the long term, however, the stents did not improve patients' survival rates. And when Swedish doctors examined a computer registry of every Swedish stent patient for the years 2003 and 2004 nearly 20,000 people they found that patients with drug-coated stents were slightly more likely to die than those with bare-metal ones.
The information published today has been presented piecemeal at conferences and meetings over the past several months, most prominently at an expert panel convened in December by the Food and Drug Administration to discuss the long-term safety of the devices. But until now it had not yet appeared in any of the peer-reviewed journals widely read by doctors.
Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center in Boston who chairs the FDA's panel on cardiovascular devices, said the new studies would likely push doctors to be more cautious about using drug-coated stents. "The decision to put in a drug-eluting stent is now a decision, where before it was used in almost any case," he said.
Sales figures suggest doctors already are being more conservative about the use of drug-coated stents. Several months ago, many hospitals reported doctors were choosing drug-coated stents in as many as 90 percent of all procedures. A recent hospital survey suggested that number had dropped to 72 percent. In other countries, where drug-coated stents were never as widely adopted, the rates are lower still.
The drop in usage has triggered a stock slide for Boston Scientific, which depends heavily on the profits from drug-coated stents.
Stents are used in coronary angioplasties, a common artery-clearing procedure that has replaced bypass surgery for many patients as a way to restore blood flow to the heart. Typically patients receive one or more stents to keep cleared arteries open. The stent implant is permanent, sealing into the artery wall.
Drug-coated versions cost more than $2000, on average. Bare-metal stents typically cost $700. In its early trials, the drug-coated version clearly helped reduce the rate at which the arteries re-clogged. But as time has passed, long-term data show higher risks. The reasons are not conclusively known, although small studies on autopsied arteries suggest that the drug coating appears to impede normal healing of the artery wall.
Patients can minimize the risk of blood clots by taking aspirin and the blood-thinning medication Plavix, although doctors and the FDA have not reached consensus on how long the medicine should be prescribed.
Four of the articles published today are examinations of long-term data from the so-called "pivotal trials," the original stent studies sponsored by manufacturers. Overall, the articles found drug-coated stents were roughly as safe as bare-metal stents for the first year after the procedure, and helped patients avoid repeat procedures. Starting a year after the procedure, however, patients with drug-coated stents could expect a slightly higher risk of dangerous coronary blood clots. Overall heart attacks and death rates were roughly equivalent for patients with the two types of stents.
But those studies were limited to patients with relatively simple angioplasty problems. More than half of angioplasty heart patients in the US have more complex problems and it remains unclear whether they can count on the same results. The Swedish study, which analyzed a so-called "real-world" registry of patients, included a broader mixture of patients and found patients with drug-coated stents had an 18 percent higher risk of death than those with bare-metal stents.
In a statement, Boston Scientific said today that most of the study results confirmed its findings that drug-coated stents are safe and effective when used as approved by the FDA. A company executive singled out the Swedish study as "far from definitive" because it was an uncontrolled registry of patients rather than a randomized clinical trial.
Both Boston Scientific and Johnson & Johnson, the other major stent maker, are sponsoring further trials to assess the safety and effectiveness of stents in more complex patients.
Dr. Steven Nissen , chairman of cardiovascular medicine at the Cleveland Clinic and president of the American College of Cardiology, said the new papers highlight a "knowledge gap" in how stents really affect patients. "Even though drug-eluting stents have been implanted in millions of patients, they've only been studied in a few thousand," he said.
Nissen and Maisel said that the new results also point to a flaw in the system for distributing information about medical devices. Under current rules, companies control the data that emerges from studies they sponsor. After the clotting controversy erupted at medical meetings this year, both major stentmakers, Boston Scientific and Johnson & Johnson, released their data to independent researchers.
"It's not enough to collect that information," said Maisel. "It needs to be collected and shared."
Since their introduction in 2003, the tiny wire tubes, about the size of a pen spring, have become fastest-selling medical devices in history, used in millions of people worldwide. They have been a boon to Boston Scientific Corp. of Natick, the largest life-science company in Massachusetts and one of the world's two major stent manufacturers.
However, safety concerns have emerged in the past year because drug-coated stents appear to carry a higher long-term risk of blood clots forming in the arteries that nourish the heart.
A series of studies released today by the New England Journal of Medicine showed that drug-coated stents carried one clear benefit: patients who receive them are less likely to return to the hospital for a repeat heart-clearing procedure.
Viewed over the long term, however, the stents did not improve patients' survival rates. And when Swedish doctors examined a computer registry of every Swedish stent patient for the years 2003 and 2004 nearly 20,000 people they found that patients with drug-coated stents were slightly more likely to die than those with bare-metal ones.
The information published today has been presented piecemeal at conferences and meetings over the past several months, most prominently at an expert panel convened in December by the Food and Drug Administration to discuss the long-term safety of the devices. But until now it had not yet appeared in any of the peer-reviewed journals widely read by doctors.
Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center in Boston who chairs the FDA's panel on cardiovascular devices, said the new studies would likely push doctors to be more cautious about using drug-coated stents. "The decision to put in a drug-eluting stent is now a decision, where before it was used in almost any case," he said.
Sales figures suggest doctors already are being more conservative about the use of drug-coated stents. Several months ago, many hospitals reported doctors were choosing drug-coated stents in as many as 90 percent of all procedures. A recent hospital survey suggested that number had dropped to 72 percent. In other countries, where drug-coated stents were never as widely adopted, the rates are lower still.
The drop in usage has triggered a stock slide for Boston Scientific, which depends heavily on the profits from drug-coated stents.
Stents are used in coronary angioplasties, a common artery-clearing procedure that has replaced bypass surgery for many patients as a way to restore blood flow to the heart. Typically patients receive one or more stents to keep cleared arteries open. The stent implant is permanent, sealing into the artery wall.
Drug-coated versions cost more than $2000, on average. Bare-metal stents typically cost $700. In its early trials, the drug-coated version clearly helped reduce the rate at which the arteries re-clogged. But as time has passed, long-term data show higher risks. The reasons are not conclusively known, although small studies on autopsied arteries suggest that the drug coating appears to impede normal healing of the artery wall.
Patients can minimize the risk of blood clots by taking aspirin and the blood-thinning medication Plavix, although doctors and the FDA have not reached consensus on how long the medicine should be prescribed.
Four of the articles published today are examinations of long-term data from the so-called "pivotal trials," the original stent studies sponsored by manufacturers. Overall, the articles found drug-coated stents were roughly as safe as bare-metal stents for the first year after the procedure, and helped patients avoid repeat procedures. Starting a year after the procedure, however, patients with drug-coated stents could expect a slightly higher risk of dangerous coronary blood clots. Overall heart attacks and death rates were roughly equivalent for patients with the two types of stents.
But those studies were limited to patients with relatively simple angioplasty problems. More than half of angioplasty heart patients in the US have more complex problems and it remains unclear whether they can count on the same results. The Swedish study, which analyzed a so-called "real-world" registry of patients, included a broader mixture of patients and found patients with drug-coated stents had an 18 percent higher risk of death than those with bare-metal stents.
In a statement, Boston Scientific said today that most of the study results confirmed its findings that drug-coated stents are safe and effective when used as approved by the FDA. A company executive singled out the Swedish study as "far from definitive" because it was an uncontrolled registry of patients rather than a randomized clinical trial.
Both Boston Scientific and Johnson & Johnson, the other major stent maker, are sponsoring further trials to assess the safety and effectiveness of stents in more complex patients.
Dr. Steven Nissen , chairman of cardiovascular medicine at the Cleveland Clinic and president of the American College of Cardiology, said the new papers highlight a "knowledge gap" in how stents really affect patients. "Even though drug-eluting stents have been implanted in millions of patients, they've only been studied in a few thousand," he said.
Nissen and Maisel said that the new results also point to a flaw in the system for distributing information about medical devices. Under current rules, companies control the data that emerges from studies they sponsor. After the clotting controversy erupted at medical meetings this year, both major stentmakers, Boston Scientific and Johnson & Johnson, released their data to independent researchers.
"It's not enough to collect that information," said Maisel. "It needs to be collected and shared."
Friday, January 26, 2007
Drug-coated stent patients urged to use anti-clotting drugs
Heart patients who had drug-coated stents inserted to prop open blocked coronary arteries should stay on anti-clotting drugs for at least a year, several doctor groups said in an advisory issued last Tuesday.
The advisory recommends that doctors tell their patients to take an anti-clotting drug like Plavix and aspirin for a year to reduce the risk of clotting, which could lead to a heart attack or death. The long-term safety of Plavix in stent patients has not been established.
Drug-coated stents are often chosen over bare metal stents because they slowly release medication that reduces the chance of arteries reclogging, which can mean follow-up surgery. However, the newer stents mean a small but significant increased risk of clotting.
The new advisory cited research showing blood clots in up to 29 percent of patients who stopped anti-clotting drugs early after receiving a drug-coated stent. The doctors also cited a study of 500 patients who received the drug-coated stents after a heart attack in which the death rate over the next 11 months was 7.5 percent for those who stopped taking anti-clotting medication compared to 0.7 percent for those who continued the regimen.
The recent information on drug-coated stents and the recommended drug regimen of up to a year means more dialogue between patients and doctors, said Dr. Cindy Grines, chair of the advisory writing committee.
The recent publicity about drug-coated stents is on patients’ minds, said Dr. John Warner, medical director of the heart, lung and vascular center at the University of Texas Southwestern Medical Center.
“Patients are very informed about this and most are asking the question before we even begin the conversation with them, which is good,” he said.
The new information means that before stent surgery, doctors must discuss with the patient whether there’s any reason they might not be able to keep up the drug regimen for at least a year, said Warner. If the cost of the drug Plavix is $4 a day or an upcoming surgery would require stopping the drug, he said it might be best to use a bare metal stent.
The advisory issued by the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons and the American Dental Association urges patients delay elective surgery for a year.
The advisory recommends that doctors tell their patients to take an anti-clotting drug like Plavix and aspirin for a year to reduce the risk of clotting, which could lead to a heart attack or death. The long-term safety of Plavix in stent patients has not been established.
Drug-coated stents are often chosen over bare metal stents because they slowly release medication that reduces the chance of arteries reclogging, which can mean follow-up surgery. However, the newer stents mean a small but significant increased risk of clotting.
The new advisory cited research showing blood clots in up to 29 percent of patients who stopped anti-clotting drugs early after receiving a drug-coated stent. The doctors also cited a study of 500 patients who received the drug-coated stents after a heart attack in which the death rate over the next 11 months was 7.5 percent for those who stopped taking anti-clotting medication compared to 0.7 percent for those who continued the regimen.
The recent information on drug-coated stents and the recommended drug regimen of up to a year means more dialogue between patients and doctors, said Dr. Cindy Grines, chair of the advisory writing committee.
The recent publicity about drug-coated stents is on patients’ minds, said Dr. John Warner, medical director of the heart, lung and vascular center at the University of Texas Southwestern Medical Center.
“Patients are very informed about this and most are asking the question before we even begin the conversation with them, which is good,” he said.
The new information means that before stent surgery, doctors must discuss with the patient whether there’s any reason they might not be able to keep up the drug regimen for at least a year, said Warner. If the cost of the drug Plavix is $4 a day or an upcoming surgery would require stopping the drug, he said it might be best to use a bare metal stent.
The advisory issued by the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons and the American Dental Association urges patients delay elective surgery for a year.
Tuesday, January 2, 2007
Making Sense of Drug-Coated Stents
When the FDA approved the use of drug-coated stents on April 24, 2003, it was hailed as a landmark advance in the treatment of blocked arteries.
“Drug-coated stents will be the new standard of cardiovascular care essentially immediately upon their release,” Dr. Campbell Rogers, director of the Cardiac Catheterization Laboratory at Brigham and Women’s Hospital (BWH), said at the time. House and Human Services Secretary Tommy Thompson called the decision “a significant step forward in the treatment of heart disease” while Mark McClellan, FDA Commissioner during that period, added that “drug-eluting stents combine drugs with medical devices to provide more effective care for many patients with heart disease. FDA is working to make sure its regulatory procedures encourage the quick and efficient approval of such safe and effective combination products.”
Significantly, the FDA’s announcement also made the following claim: “The types of adverse events seen with the drug-eluting stent were similar to those that occurred with the uncoated stent.” However, only three and a half years later, that statement is being challenged by a growing number of medical professionals, researchers, and consumer watchdogs who fear that the drug-coated device brings with it a higher risk of blood clots that can lead to heart attacks and strokes. Today, the questionable safety of drug-coated stents threatens to shake up this multibillion-dollar industry, raising a myriad of medical and legal issues.
On December 7 and 8, the FDA held a public Circulatory System Devices Advisory Panel meeting to discuss the issue and delivered the kind of mixed message that is typical at the FDA: Drug-coated stents were deemed safe for a certain subset of the patient population, but were also associated with a higher risk of blood clots, heart attacks, and death in the majority of patients. The panel recommended that the FDA issue new warnings for doctors and patients to reflect the elevated risk. The panel also sought to reduce instances of “off-label” usage, which accounts for more than half of the drug-coated stent market. Yet they saw no compelling reason to pull the controversial devices off the market.
In the long run, however, this may not be good news for stent makers. “Increased incidents of injury and adverse events are always important factors to examine when assessing the liability case against the manufacturers of drugs or medical devices,” says Jason Mark, an attorney at Parker & Waichman LLP who runs the firm’s mass tort unit. “With safer alternative designs available to patients that pose less thrombotic risk, manufacturers who place these products into the stream of commerce do so at their own peril and, unfortunately, at the peril of unsuspecting patients.”
In 2003, the news was all good for Cordis Corporation, the division of Johnson & Johnson that developed the drug-eluting stent (DES). At the time, the only stents in use were bare-metal stents (BMS). These devices–a kind of wire-mesh scaffolding–were used to prop open clogged arteries after angioplasty and had met with much success. However, according to the FDA, roughly 15 to 30 percent of stent patients suffered from restenosis (re-clogging of the artery) within a year of the procedure and had to be treated again with another angioplasty or bypass surgery.
The drug-eluting stent was developed to solve the problem of restenosis. By releasing a drug to retard cell growth and stop scar tissue from forming within arteries that have been opened, the new device was designed to prevent the arteries from becoming blocked again. Cordis had funded a national clinical trial to test the device’s effectiveness, and it was lauded as highly successful. The combined occurrence of repeat angioplasty, bypass surgery, heart attacks, and death was 8.8 percent for drug-eluting stent patients and 21 percent for the uncoated stent patients. The FDA said the new device was found to “significantly reduce the rate of re-blockage that occurs with existing stents.” BWH’s Dr. Rogers, who had been involved in the New England-based part of the trial, noted, “When we tested the drug-coated devices versus the plain metal version on patients, the results were very compelling. In approximately 95 percent of patients receiving the drug-coated stents, restenosis was prevented.”
Patients and medical professionals were so excited about the drug-coated stent that angioplasty procedures were being delayed specifically to await the FDA’s approval of the Cypher, Cordis’ revolutionary Sirolimus-Eluting Coronary Stent. The FDA issued its blessing in April of 2003, and by June, the device was already in short supply as demand soared. Patients had heard the news about drug-eluting stents, and suddenly, nobody wanted a bare-metal stent anymore.
It didn’t take long for the mood to change. In early July of 2003, less than three months after it approved the Cypher stent, the FDA issued its first warning about the product. In a July 8 alert, the agency stated: “Since the product’s introduction it is estimated that over 50,000 patients have received a Cypher stent. To date, FDA has received 47 Medical Device Reports (MDRs) of stent thrombosis occurring at the time of implantation or within a few days of implantation.”
Cordis sent a letter to healthcare professionals that week, notifying them of the incidence of thrombosis and reminding them of four important considerations with regard to using the Cypher: selection of the appropriate stent size; selection of appropriate patients for implantation; use of an adequate antiplatelet regimen to reduce the risk of clot formation; and the use of the proper technique for stent deployment. The third recommendation–the one related to blood clotting–would become a key element in the implantation and maintenance of drug-coated stents.
The news only got worse. On October 29, 2003, the FDA felt compelled to issue a second warning about the new device. The agency had by then received nearly 300 reports of adverse effects, 60 of which resulted in fatalities. In addition, there had been 50 reports of hypersensitivity and allergic reactions including pain, rash, respiratory alterations, hives, itching, fever, and blood pressure changes; several of these events proved fatal as well. Only a month later, the FDA provided updated numbers. They’d received 75 new reports of thrombosis and 20 new incidents of hypersensitivity. Meanwhile, Cordis had distributed nearly 600,000 Cypher stents by that point, pumping them out at well more than 100,000 a month.
Doctors and patients proceeded with little caution over the next year, putting aside fears of thrombosis and other complications, and the popularity of the drug-eluting stent continued to grow. After gaining FDA approval in March of 2004, Boston Scientific introduced its own drug-coated stent, the Taxus, coated with paclitaxel. On October 18, 2004, a year after it issued its second DES warning, the FDA announced its conclusion that there was virtually no difference in the thrombosis risks of drug-eluting stents when compared to bare-metal stents.
“The Cypher stent,” said the agency, “when implanted in accordance with the approved indications for use, is not associated with an excess of SATs [sub-acute thromboses] compared to bare-metal stents. SAT remains a relatively rare event that occurs within the first 30 days following the stenting procedure.”
While the safety of the DES may still have been questioned, the efficacy of the product was almost universally accepted: Drug-coated stents were instrumental in reducing the need for second surgical procedures. By the end of 2005, more than 90 percent of all stents being implanted in heart patients were drug-eluting stents.
Medical professionals were so thrilled that drug-coated stents reduced the risk of restenosis, they were perhaps willing to overlook the fact that the risk of stent thrombosis may have been growing. Several studies released in 2006 have brought the safety concerns back to the forefront of the discussion.
The first significant study was the BASKET-LATE (Basel Stent Kosten Effektivitäts Trial-Late Thrombotic Events) trial, which was set up to assess rates of cardiac death and myocardial infarction (MI) in stent patients who stopped using clopidogrel, the anti-clotting drug sold under the brand name Plavix. The randomized observational study fitted 499 patients with a DES and 244 with a BMS. According to the study results, in the year after clopidogrel discontinuation, patients with drug-eluting stents were twice as likely to suffer late stent thrombosis as those with bare-metal stents. Researchers also concluded that the risk of cardiac death or MI with the use of drug-eluting stents was “significantly higher” than the risk with the use of bare-metal stents: 4.9 percent versus 1.3 percent in the year after clopidogrel discontinuation.
Dr. Matthias E. Pfisterer created quite a stir when he first presented these results in March of 2006 at the Annual Scientific Session of the American College of Cardiology in Atlanta, and since that point, the debate has only gotten more heated. In September, the issue commanded center stage at the European Society of Cardiology/World Congress of Cardiology meeting in Barcelona, Spain, when three separate European studies questioned the long-term safety of drug-eluting stents.
The major presentation was made by Dr. Edoardo Camenzind of the University Hospital in Geneva. Dr. Camenzind conducted a meta-analysis of nine clinical trials and more than 5,000 patients to determine the risks of the DES versus the BMS. Camenzind found that the incidence of death or heart attack was higher for DES patients than for BMS patients–and higher for Cypher patients than for Taxus patients. Cypher patients were as much as 30 to 40 percent more likely to suffer serious adverse events than those with bare-metal stents while Taxus elevated the risks roughly 5 to 10 percent.
A second meta-analysis came from Dr. Alain J. Nordmann of the University Hospital in Basel. In this study, researchers examined 17 randomized trials and found that the Cypher was associated with significantly higher rates of noncardiac death when compared to bare-metal stents. The ThoraxCenter of Rotterdam presented its own study, which tracked stent thrombosis rates in more than 8,000 patients. Dr. Peter Wenaweser reported the cumulative rate of thrombosis was 2.9 percent, not terribly significant, but the troubling news was that the risk of thrombosis did not seem to lessen over time. Instead, the risk associated with DES patients continued to increase at the same rate (roughly 0.6 percent) year by year.
The biggest bomb at the September conference in Barcelona was dropped by Boston Scientific itself. The stent manufacturer announced that its own internal research had found a slightly higher, statistically noteworthy risk of blood clotting in patients who received their Taxus drug-eluting stents when compared to those who’d been implanted with bare-metal stents. Their review looked at 3,500 patients and included four years’ worth of data to determine the risks of late stent thrombosis (blood clotting in the stent area from the period beginning six months after implantation). Their admission was the first of its kind by any of the stent makers.
Immediately following the Barcelona meetings, the FDA decided to issue a new statement regarding drug-eluting stents. “We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES,” the agency said, specifically citing the BASKET-LATE trial and Dr. Camenzind’s meta-analysis. “The small but significant increase in the rate of death and myocardial infarction observed in these studies was noted in patients followed 18 months to 3 years after stent implantation.”
The agency stressed the need for further studies and noted the importance of effective Plavix regimens to prevent clotting in DES patients. They also announced December’s public meeting of the Circulatory System Devices Advisory Panel to discuss the issues in greater detail. But ultimately, the agency was quite clear when it said: “At this time, FDA believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications. These devices have significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year.”
The issue gained momentum in October at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, D.C. A highly anticipated presentation by Drs. Gregg W. Stone and Marty Leon further clouded the medical issues at hand. Yes, they said, drug-eluting stents were indeed associated with significantly higher rates of late stent thrombosis. Yet, notably, they also claimed that the mortality rates among DES patients were no higher than those of BMS patients. That was largely because BMS patients were more than twice as likely to suffer re-clogging of their arteries.
With the debate raging on and contradictory evidence mounting, the stage was set for the FDA’s public meeting in December. The fate of the $6 billion DES industry largely hung in the balance.
The FDA’s public meeting of the Circulatory System Devices Advisory Panel on December 8 and 9 was not without its own share of controversy.
For one thing, the FDA decided to use physicians with a monetary stake in the products they were reviewing on behalf of the agency. Six doctors on the advisory panel had financial links to stent makers Johnson & Johnson and Boston Scientific; the FDA granted conflict-of-interest waivers to all six of the physicians in question.
“The reality is that the FDA sees industry as its client,” notes Jason Mark, the Parker & Waichman attorney. “The interests of the FDA are too often aligned with the interests of industry, and it’s the patients who time and time again suffer the consequences.”
Considering who was chosen for the panel, perhaps it’s not surprising that the group recommended, for the most part, a wait-and-see, business-as-usual approach. The panel did recommend new label warnings highlighting the increase in the risk of sudden heart attack or death in DES patients. Yet, in its own inimitable way, the FDA managed only to complicate matters by adding fuel to both sides of the DES argument.
While some physicians feel the devices may be too risky for the marketplace, others feel that the new warnings may discourage potential DES recipients who would truly benefit. Meanwhile, new studies continue to emerge with regard to the increased risk of thrombosis in DES patients; a recent Cleveland Clinic review assessed the risk of thrombosis in DES patients as being four to five times greater than that of BMS patients.
With millions and millions of patients already having received drug-coated stents–some estimates put the total number of DES patients as high as 6 million–even a very small increase in the risk of thrombosis becomes all the more significant. Writing in Cardiosource, the website of the American College of Cardiology, Drs. Sanjay Kaul and George A. Diamond noted that, based on the available evidence, drug-eluting stents may be responsible for more than 2,000 additional deaths every year when you consider the fact that roughly 1 million Americans per year receive a DES.
“Our romance with new technology–DES being only the most recent instance–is entirely understandable,” Drs. Kaul and Diamond write. “Technological innovation accounts for much of the miracle in modern medicine. It is entirely understandable, then, that: 1) device companies should want to develop new technology and support clinical trials necessary for regulatory approval and marketing so as to profit from the sale of that technology in a capitalistic market; 2) medical investigators should want to perform and publish such studies as a way to advance their careers; 3) insurance companies should want to rely on this information to justify reimbursing hospitals and physicians for utilization of that technology lest they be charged with restricting access to care in return for reducing their costs; and 4) hospitals and physicians should want to employ such state-of-the-art technology, and that patients should demand its use–even before long-term outcome trials confirm the short-term promise of that technology.
“Together, 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.”
While those two doctors don’t believe a recall or moratorium on DES is necessary, they do support further FDA review and the resulting labeling changes as well as “a more accurate, timely, and comprehensive post-market surveillance program.” They also believe the FDA should be doing more to curtail off-label uses, which still account for more than half of DES implantation. “Although the FDA does not have the mandate to impact medical practice,” they note, “it should nevertheless leverage its relationships with medical professional societies and device sponsors to collaborate on the development and implementation of new tools and programs that help mitigate unnecessary risk and promulgate best practice standards.”
If nothing else, the DES debate has assured that most healthcare professionals will be more vigilant and discerning when addressing the risks and benefits of DES usage. Based on the available findings, doctors should only recommend drug-eluting stents for patients with a high risk of restenosis or those patients who cannot or will not handle long-term antiplatelet therapy. Doctors should not be afraid to employ bare-metal stents in certain cases where the DES may prove too risky. (Since bare-metal stents can be three to four times cheaper than drug-coated stents, the issue may have financial ramifications as well.)
The use of clopidogrel (Plavix) has proven to be essential to the long-term health of DES patients. However, the FDA has not yet approved the drug for that usage, meaning that DES recipients must use the drug off-label. Mostly all parties agree that extending the antiplatelet therapy in DES patients may be necessary in order to prevent dangerous blood clotting.
As with any new drug, therapy, or device, long-term side effects may take years to reveal themselves. The hope is that the increased scrutiny facing drug-eluting stents will lead to better decisions by the medical community, further research by the manufacturers, and greater understanding and awareness on the part of patients themselves.
“Drug-coated stents will be the new standard of cardiovascular care essentially immediately upon their release,” Dr. Campbell Rogers, director of the Cardiac Catheterization Laboratory at Brigham and Women’s Hospital (BWH), said at the time. House and Human Services Secretary Tommy Thompson called the decision “a significant step forward in the treatment of heart disease” while Mark McClellan, FDA Commissioner during that period, added that “drug-eluting stents combine drugs with medical devices to provide more effective care for many patients with heart disease. FDA is working to make sure its regulatory procedures encourage the quick and efficient approval of such safe and effective combination products.”
Significantly, the FDA’s announcement also made the following claim: “The types of adverse events seen with the drug-eluting stent were similar to those that occurred with the uncoated stent.” However, only three and a half years later, that statement is being challenged by a growing number of medical professionals, researchers, and consumer watchdogs who fear that the drug-coated device brings with it a higher risk of blood clots that can lead to heart attacks and strokes. Today, the questionable safety of drug-coated stents threatens to shake up this multibillion-dollar industry, raising a myriad of medical and legal issues.
On December 7 and 8, the FDA held a public Circulatory System Devices Advisory Panel meeting to discuss the issue and delivered the kind of mixed message that is typical at the FDA: Drug-coated stents were deemed safe for a certain subset of the patient population, but were also associated with a higher risk of blood clots, heart attacks, and death in the majority of patients. The panel recommended that the FDA issue new warnings for doctors and patients to reflect the elevated risk. The panel also sought to reduce instances of “off-label” usage, which accounts for more than half of the drug-coated stent market. Yet they saw no compelling reason to pull the controversial devices off the market.
In the long run, however, this may not be good news for stent makers. “Increased incidents of injury and adverse events are always important factors to examine when assessing the liability case against the manufacturers of drugs or medical devices,” says Jason Mark, an attorney at Parker & Waichman LLP who runs the firm’s mass tort unit. “With safer alternative designs available to patients that pose less thrombotic risk, manufacturers who place these products into the stream of commerce do so at their own peril and, unfortunately, at the peril of unsuspecting patients.”
In 2003, the news was all good for Cordis Corporation, the division of Johnson & Johnson that developed the drug-eluting stent (DES). At the time, the only stents in use were bare-metal stents (BMS). These devices–a kind of wire-mesh scaffolding–were used to prop open clogged arteries after angioplasty and had met with much success. However, according to the FDA, roughly 15 to 30 percent of stent patients suffered from restenosis (re-clogging of the artery) within a year of the procedure and had to be treated again with another angioplasty or bypass surgery.
The drug-eluting stent was developed to solve the problem of restenosis. By releasing a drug to retard cell growth and stop scar tissue from forming within arteries that have been opened, the new device was designed to prevent the arteries from becoming blocked again. Cordis had funded a national clinical trial to test the device’s effectiveness, and it was lauded as highly successful. The combined occurrence of repeat angioplasty, bypass surgery, heart attacks, and death was 8.8 percent for drug-eluting stent patients and 21 percent for the uncoated stent patients. The FDA said the new device was found to “significantly reduce the rate of re-blockage that occurs with existing stents.” BWH’s Dr. Rogers, who had been involved in the New England-based part of the trial, noted, “When we tested the drug-coated devices versus the plain metal version on patients, the results were very compelling. In approximately 95 percent of patients receiving the drug-coated stents, restenosis was prevented.”
Patients and medical professionals were so excited about the drug-coated stent that angioplasty procedures were being delayed specifically to await the FDA’s approval of the Cypher, Cordis’ revolutionary Sirolimus-Eluting Coronary Stent. The FDA issued its blessing in April of 2003, and by June, the device was already in short supply as demand soared. Patients had heard the news about drug-eluting stents, and suddenly, nobody wanted a bare-metal stent anymore.
It didn’t take long for the mood to change. In early July of 2003, less than three months after it approved the Cypher stent, the FDA issued its first warning about the product. In a July 8 alert, the agency stated: “Since the product’s introduction it is estimated that over 50,000 patients have received a Cypher stent. To date, FDA has received 47 Medical Device Reports (MDRs) of stent thrombosis occurring at the time of implantation or within a few days of implantation.”
Cordis sent a letter to healthcare professionals that week, notifying them of the incidence of thrombosis and reminding them of four important considerations with regard to using the Cypher: selection of the appropriate stent size; selection of appropriate patients for implantation; use of an adequate antiplatelet regimen to reduce the risk of clot formation; and the use of the proper technique for stent deployment. The third recommendation–the one related to blood clotting–would become a key element in the implantation and maintenance of drug-coated stents.
The news only got worse. On October 29, 2003, the FDA felt compelled to issue a second warning about the new device. The agency had by then received nearly 300 reports of adverse effects, 60 of which resulted in fatalities. In addition, there had been 50 reports of hypersensitivity and allergic reactions including pain, rash, respiratory alterations, hives, itching, fever, and blood pressure changes; several of these events proved fatal as well. Only a month later, the FDA provided updated numbers. They’d received 75 new reports of thrombosis and 20 new incidents of hypersensitivity. Meanwhile, Cordis had distributed nearly 600,000 Cypher stents by that point, pumping them out at well more than 100,000 a month.
Doctors and patients proceeded with little caution over the next year, putting aside fears of thrombosis and other complications, and the popularity of the drug-eluting stent continued to grow. After gaining FDA approval in March of 2004, Boston Scientific introduced its own drug-coated stent, the Taxus, coated with paclitaxel. On October 18, 2004, a year after it issued its second DES warning, the FDA announced its conclusion that there was virtually no difference in the thrombosis risks of drug-eluting stents when compared to bare-metal stents.
“The Cypher stent,” said the agency, “when implanted in accordance with the approved indications for use, is not associated with an excess of SATs [sub-acute thromboses] compared to bare-metal stents. SAT remains a relatively rare event that occurs within the first 30 days following the stenting procedure.”
While the safety of the DES may still have been questioned, the efficacy of the product was almost universally accepted: Drug-coated stents were instrumental in reducing the need for second surgical procedures. By the end of 2005, more than 90 percent of all stents being implanted in heart patients were drug-eluting stents.
Medical professionals were so thrilled that drug-coated stents reduced the risk of restenosis, they were perhaps willing to overlook the fact that the risk of stent thrombosis may have been growing. Several studies released in 2006 have brought the safety concerns back to the forefront of the discussion.
The first significant study was the BASKET-LATE (Basel Stent Kosten Effektivitäts Trial-Late Thrombotic Events) trial, which was set up to assess rates of cardiac death and myocardial infarction (MI) in stent patients who stopped using clopidogrel, the anti-clotting drug sold under the brand name Plavix. The randomized observational study fitted 499 patients with a DES and 244 with a BMS. According to the study results, in the year after clopidogrel discontinuation, patients with drug-eluting stents were twice as likely to suffer late stent thrombosis as those with bare-metal stents. Researchers also concluded that the risk of cardiac death or MI with the use of drug-eluting stents was “significantly higher” than the risk with the use of bare-metal stents: 4.9 percent versus 1.3 percent in the year after clopidogrel discontinuation.
Dr. Matthias E. Pfisterer created quite a stir when he first presented these results in March of 2006 at the Annual Scientific Session of the American College of Cardiology in Atlanta, and since that point, the debate has only gotten more heated. In September, the issue commanded center stage at the European Society of Cardiology/World Congress of Cardiology meeting in Barcelona, Spain, when three separate European studies questioned the long-term safety of drug-eluting stents.
The major presentation was made by Dr. Edoardo Camenzind of the University Hospital in Geneva. Dr. Camenzind conducted a meta-analysis of nine clinical trials and more than 5,000 patients to determine the risks of the DES versus the BMS. Camenzind found that the incidence of death or heart attack was higher for DES patients than for BMS patients–and higher for Cypher patients than for Taxus patients. Cypher patients were as much as 30 to 40 percent more likely to suffer serious adverse events than those with bare-metal stents while Taxus elevated the risks roughly 5 to 10 percent.
A second meta-analysis came from Dr. Alain J. Nordmann of the University Hospital in Basel. In this study, researchers examined 17 randomized trials and found that the Cypher was associated with significantly higher rates of noncardiac death when compared to bare-metal stents. The ThoraxCenter of Rotterdam presented its own study, which tracked stent thrombosis rates in more than 8,000 patients. Dr. Peter Wenaweser reported the cumulative rate of thrombosis was 2.9 percent, not terribly significant, but the troubling news was that the risk of thrombosis did not seem to lessen over time. Instead, the risk associated with DES patients continued to increase at the same rate (roughly 0.6 percent) year by year.
The biggest bomb at the September conference in Barcelona was dropped by Boston Scientific itself. The stent manufacturer announced that its own internal research had found a slightly higher, statistically noteworthy risk of blood clotting in patients who received their Taxus drug-eluting stents when compared to those who’d been implanted with bare-metal stents. Their review looked at 3,500 patients and included four years’ worth of data to determine the risks of late stent thrombosis (blood clotting in the stent area from the period beginning six months after implantation). Their admission was the first of its kind by any of the stent makers.
Immediately following the Barcelona meetings, the FDA decided to issue a new statement regarding drug-eluting stents. “We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES,” the agency said, specifically citing the BASKET-LATE trial and Dr. Camenzind’s meta-analysis. “The small but significant increase in the rate of death and myocardial infarction observed in these studies was noted in patients followed 18 months to 3 years after stent implantation.”
The agency stressed the need for further studies and noted the importance of effective Plavix regimens to prevent clotting in DES patients. They also announced December’s public meeting of the Circulatory System Devices Advisory Panel to discuss the issues in greater detail. But ultimately, the agency was quite clear when it said: “At this time, FDA believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications. These devices have significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year.”
The issue gained momentum in October at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, D.C. A highly anticipated presentation by Drs. Gregg W. Stone and Marty Leon further clouded the medical issues at hand. Yes, they said, drug-eluting stents were indeed associated with significantly higher rates of late stent thrombosis. Yet, notably, they also claimed that the mortality rates among DES patients were no higher than those of BMS patients. That was largely because BMS patients were more than twice as likely to suffer re-clogging of their arteries.
With the debate raging on and contradictory evidence mounting, the stage was set for the FDA’s public meeting in December. The fate of the $6 billion DES industry largely hung in the balance.
The FDA’s public meeting of the Circulatory System Devices Advisory Panel on December 8 and 9 was not without its own share of controversy.
For one thing, the FDA decided to use physicians with a monetary stake in the products they were reviewing on behalf of the agency. Six doctors on the advisory panel had financial links to stent makers Johnson & Johnson and Boston Scientific; the FDA granted conflict-of-interest waivers to all six of the physicians in question.
“The reality is that the FDA sees industry as its client,” notes Jason Mark, the Parker & Waichman attorney. “The interests of the FDA are too often aligned with the interests of industry, and it’s the patients who time and time again suffer the consequences.”
Considering who was chosen for the panel, perhaps it’s not surprising that the group recommended, for the most part, a wait-and-see, business-as-usual approach. The panel did recommend new label warnings highlighting the increase in the risk of sudden heart attack or death in DES patients. Yet, in its own inimitable way, the FDA managed only to complicate matters by adding fuel to both sides of the DES argument.
While some physicians feel the devices may be too risky for the marketplace, others feel that the new warnings may discourage potential DES recipients who would truly benefit. Meanwhile, new studies continue to emerge with regard to the increased risk of thrombosis in DES patients; a recent Cleveland Clinic review assessed the risk of thrombosis in DES patients as being four to five times greater than that of BMS patients.
With millions and millions of patients already having received drug-coated stents–some estimates put the total number of DES patients as high as 6 million–even a very small increase in the risk of thrombosis becomes all the more significant. Writing in Cardiosource, the website of the American College of Cardiology, Drs. Sanjay Kaul and George A. Diamond noted that, based on the available evidence, drug-eluting stents may be responsible for more than 2,000 additional deaths every year when you consider the fact that roughly 1 million Americans per year receive a DES.
“Our romance with new technology–DES being only the most recent instance–is entirely understandable,” Drs. Kaul and Diamond write. “Technological innovation accounts for much of the miracle in modern medicine. It is entirely understandable, then, that: 1) device companies should want to develop new technology and support clinical trials necessary for regulatory approval and marketing so as to profit from the sale of that technology in a capitalistic market; 2) medical investigators should want to perform and publish such studies as a way to advance their careers; 3) insurance companies should want to rely on this information to justify reimbursing hospitals and physicians for utilization of that technology lest they be charged with restricting access to care in return for reducing their costs; and 4) hospitals and physicians should want to employ such state-of-the-art technology, and that patients should demand its use–even before long-term outcome trials confirm the short-term promise of that technology.
“Together, 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.”
While those two doctors don’t believe a recall or moratorium on DES is necessary, they do support further FDA review and the resulting labeling changes as well as “a more accurate, timely, and comprehensive post-market surveillance program.” They also believe the FDA should be doing more to curtail off-label uses, which still account for more than half of DES implantation. “Although the FDA does not have the mandate to impact medical practice,” they note, “it should nevertheless leverage its relationships with medical professional societies and device sponsors to collaborate on the development and implementation of new tools and programs that help mitigate unnecessary risk and promulgate best practice standards.”
If nothing else, the DES debate has assured that most healthcare professionals will be more vigilant and discerning when addressing the risks and benefits of DES usage. Based on the available findings, doctors should only recommend drug-eluting stents for patients with a high risk of restenosis or those patients who cannot or will not handle long-term antiplatelet therapy. Doctors should not be afraid to employ bare-metal stents in certain cases where the DES may prove too risky. (Since bare-metal stents can be three to four times cheaper than drug-coated stents, the issue may have financial ramifications as well.)
The use of clopidogrel (Plavix) has proven to be essential to the long-term health of DES patients. However, the FDA has not yet approved the drug for that usage, meaning that DES recipients must use the drug off-label. Mostly all parties agree that extending the antiplatelet therapy in DES patients may be necessary in order to prevent dangerous blood clotting.
As with any new drug, therapy, or device, long-term side effects may take years to reveal themselves. The hope is that the increased scrutiny facing drug-eluting stents will lead to better decisions by the medical community, further research by the manufacturers, and greater understanding and awareness on the part of patients themselves.
Monday, January 1, 2007
Study finds `intriguing evidence' of stents' danger
After months of alarm over the small but potentially fatal risk of blood clots forming in the coronary arteries of people who have been implanted with drug-coated stents, researchers say they may have discovered why the tiny devices can become deadly.
Drug-coated stents may hinder the heart's natural ability to form tiny collateral blood vessels that can salvage heart muscle by rerouting the blood supply, according to a new study.
This little-understood process, which is known as nature's bypass system, seems to be stunted by the medicine that coats the stents, but not by bare-metal stents, according to Swiss researchers whose study will be published Tuesday in the Journal of the American College of Cardiology.
In a study of 120 patients, there was 30 percent to 40 percent less collateral blood vessel function in those implanted with the drug-coated stents, compared with bare-metal stents, six months after implantation.
The researchers theorized that this deficit could result in more serious damage to the heart in the event an artery abruptly closed such as when a clot occurs.
"Our results show that drug-eluting (coated) stents may hamper the heart's ability to salvage its own muscles," senior author Christian Seiler, a professor and physician at University Hospital in Bern, Switzerland, said in a statement. "... This could lead to a more severe heart attack."
The study presents some "very intriguing evidence," said David Marks, an associate professor of medicine at the Medical College of Wisconsin and director of the cardiac catheterization laboratory at Froedtert Hospital in Wauwatosa, Wis.
"They are speculating from very compelling and well-done data," Marks said.
Marks said the study provides more reason for doctors to make sure they have selected the correct stent for patients with coronary artery disease.
Medical College researchers now are in the midst of their own five-year study to try to find genes linked to the heart's ability to grow new blood vessels when blockages occur.
The $6 million study funded by the National Institutes of Health will use heart catheterization films and blood samples from heart patients. About 1,200 patients from the Milwaukee area are expected to be enrolled in the study.
"Some patients develop very vigorous collaterals," Marks said. "Other patients don't."
The difference may explain why some people survive heart attacks and why others die.
The hope is that if a gene or genes are discovered, drugs that aid the process of collateral blood vessel formation may be developed.
Because the field of collateral blood-vessel formation is so poorly understood, no one suspected the results from the new study, said Morton Kern, a professor of medicine at the University of California, Irvine.
"It is one other potential downside to drug-eluting stents," Kern said.
The study likely will focus more attention on the process of collateral blood-vessel formation as well as developing new generations of drug-coated stents that don't hinder that process, he said.
When drug-coated stents became popular in 2003, they were heralded as a major breakthrough in treating heart disease. The tiny, expandable mesh-like tubes were shown to be far superior to bare-metal stents in preventing the gradual re-blockage of arteries, a troubling but seldom fatal process known as restenosis.
Drug-coated stents are covered by medicine that slowly dissolves and that can dramatically reduce the formation of scar tissue that can re-block an artery.
About 1 million Americans are implanted with stents each year and an estimated 80 percent of those devices are drug-coated.
However, in recent months researchers and regulators have amassed evidence that in a small number of patients drug-coated stents were associated with the formation of potentially deadly blood clots up to two years later.
Studies suggest that clot formation, a process known as thrombosis, occurs in 0.6 percent to 2.6 percent of patients who get drug-coated stents. Thrombosis is more common when a patient discontinues taking blood-thinning drugs.
Doctors say that even with the recent alarms about drug-coated stents, the devices still are worth the risk when used in the appropriate setting. Compared with bare-metal stents, the drug-coated devices can substantially lower the risk of an artery re-narrowing with scar tissue.
At the same time, criticism has been leveled at some cardiologists for being too quick to use the devices, especially in so-called off-label circumstances where the devices are implanted for conditions in which clinical trials have not proven their effectiveness and safety.
Drug-coated stent use results in an estimated 2,160 excess deaths in the U.S. each year, according to an October editorial in an online journal of the American College of Cardiology.
"Surely, it is time to refine the use of this innovative technology so that its benefits outweigh its cost and potential for harm," said the editorial written by two California doctors.
At the University of Wisconsin Hospital in Madison, doctors already have become much more cautious in their use of drug-coated stents because of the recent reports of clots forming in the devices, said Giorgio Gimelli, director of the hospital's cardiac catheterization laboratory.
Doctors had been using drug-coated stents about 90 percent of the time, but that has dropped to about 75 percent in recent months, he said.
"This has given us cold feet a little bit," said Gimelli, an assistant professor of medicine. "We've changed practice fairly significantly."
The new study on how drug-coated stents may affect collateral blood vessel formation adds another reason to be cautious, he said.
"We'd prefer not to see it, but it's there and we'll have to deal with it," he said.
Drug-coated stents may hinder the heart's natural ability to form tiny collateral blood vessels that can salvage heart muscle by rerouting the blood supply, according to a new study.
This little-understood process, which is known as nature's bypass system, seems to be stunted by the medicine that coats the stents, but not by bare-metal stents, according to Swiss researchers whose study will be published Tuesday in the Journal of the American College of Cardiology.
In a study of 120 patients, there was 30 percent to 40 percent less collateral blood vessel function in those implanted with the drug-coated stents, compared with bare-metal stents, six months after implantation.
The researchers theorized that this deficit could result in more serious damage to the heart in the event an artery abruptly closed such as when a clot occurs.
"Our results show that drug-eluting (coated) stents may hamper the heart's ability to salvage its own muscles," senior author Christian Seiler, a professor and physician at University Hospital in Bern, Switzerland, said in a statement. "... This could lead to a more severe heart attack."
The study presents some "very intriguing evidence," said David Marks, an associate professor of medicine at the Medical College of Wisconsin and director of the cardiac catheterization laboratory at Froedtert Hospital in Wauwatosa, Wis.
"They are speculating from very compelling and well-done data," Marks said.
Marks said the study provides more reason for doctors to make sure they have selected the correct stent for patients with coronary artery disease.
Medical College researchers now are in the midst of their own five-year study to try to find genes linked to the heart's ability to grow new blood vessels when blockages occur.
The $6 million study funded by the National Institutes of Health will use heart catheterization films and blood samples from heart patients. About 1,200 patients from the Milwaukee area are expected to be enrolled in the study.
"Some patients develop very vigorous collaterals," Marks said. "Other patients don't."
The difference may explain why some people survive heart attacks and why others die.
The hope is that if a gene or genes are discovered, drugs that aid the process of collateral blood vessel formation may be developed.
Because the field of collateral blood-vessel formation is so poorly understood, no one suspected the results from the new study, said Morton Kern, a professor of medicine at the University of California, Irvine.
"It is one other potential downside to drug-eluting stents," Kern said.
The study likely will focus more attention on the process of collateral blood-vessel formation as well as developing new generations of drug-coated stents that don't hinder that process, he said.
When drug-coated stents became popular in 2003, they were heralded as a major breakthrough in treating heart disease. The tiny, expandable mesh-like tubes were shown to be far superior to bare-metal stents in preventing the gradual re-blockage of arteries, a troubling but seldom fatal process known as restenosis.
Drug-coated stents are covered by medicine that slowly dissolves and that can dramatically reduce the formation of scar tissue that can re-block an artery.
About 1 million Americans are implanted with stents each year and an estimated 80 percent of those devices are drug-coated.
However, in recent months researchers and regulators have amassed evidence that in a small number of patients drug-coated stents were associated with the formation of potentially deadly blood clots up to two years later.
Studies suggest that clot formation, a process known as thrombosis, occurs in 0.6 percent to 2.6 percent of patients who get drug-coated stents. Thrombosis is more common when a patient discontinues taking blood-thinning drugs.
Doctors say that even with the recent alarms about drug-coated stents, the devices still are worth the risk when used in the appropriate setting. Compared with bare-metal stents, the drug-coated devices can substantially lower the risk of an artery re-narrowing with scar tissue.
At the same time, criticism has been leveled at some cardiologists for being too quick to use the devices, especially in so-called off-label circumstances where the devices are implanted for conditions in which clinical trials have not proven their effectiveness and safety.
Drug-coated stent use results in an estimated 2,160 excess deaths in the U.S. each year, according to an October editorial in an online journal of the American College of Cardiology.
"Surely, it is time to refine the use of this innovative technology so that its benefits outweigh its cost and potential for harm," said the editorial written by two California doctors.
At the University of Wisconsin Hospital in Madison, doctors already have become much more cautious in their use of drug-coated stents because of the recent reports of clots forming in the devices, said Giorgio Gimelli, director of the hospital's cardiac catheterization laboratory.
Doctors had been using drug-coated stents about 90 percent of the time, but that has dropped to about 75 percent in recent months, he said.
"This has given us cold feet a little bit," said Gimelli, an assistant professor of medicine. "We've changed practice fairly significantly."
The new study on how drug-coated stents may affect collateral blood vessel formation adds another reason to be cautious, he said.
"We'd prefer not to see it, but it's there and we'll have to deal with it," he said.
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