Evelyn Pringle September 22, 2006
Recent studies have shown the new generation of drug-eluting heart stents to be associated with an increased risk of late stent thrombosis, cardiac mortality, myocardial infarction, and all cause mortality.
And at the same time, they have proven to be little more effective, if any, than the older bare-metal stents that sell for a fraction of the cost.
Due to the discovery of all of these increased risks, experts are now predicting that patients who received the drug eluding stents will be required to take the expensive blood-thinning drug Plavix for life.
In a few short years, these new stents have become one of the best selling devices in medical history. In 2005, about 1.5 million patients were implanted with drug-eluting stents in the US alone, with the market dominated by the Taxus stent from Boston Scientific, and the Cypher from Cordis, a Johnson & Johnson company. Cypher received FDA approval in 2003, and Taxus was approved a year later.
A market analysis in the January/February 2006, issue of Medical Device Link, reported that the worldwide market for drug-eluting coronary stents reached an estimated $4.2 billion in 2004 and is expected to nearly double by 2010.
According to the May 17, 2005, Boston Globe, Boston Scientific spent a mere $350 million to develop the Taxus stent but after the FDA approved the device for sale in March 2004, the company increased sales by more than $2 billion and for 2004, posted a "whopping 62 percent increase in revenue."
The Taxus is by far the company's biggest moneymaker.
Of Johnson & Johnson's seven device units, Cordis is by far the most profit enhancing. In 2005, its sales grew 24% to $4 billion.
Financial analysts estimate that the profit margin per stent sold is between 80 and 90%. The September 18, 2006, Boston Globe said that bare-metal stents run about $800 a piece, compared to $2,200 for a drug-coated stent.
Critics have long criticized the outrageous price because according to Dr Mitchell Krucoff, of Duke Clinical Research Institute, Durham, NC, in Heartwire on February 7, 2006, "In the case of first-generation DES, these are essentially bare-metal stents that have been spray-painted with plastic." The August 6, 2004 Boston Globe describes these medical devices as:
"Stents are wire mesh devices placed in arteries, which are blocked by fatty deposits. Doctors thread a tiny balloon into the artery and inflate it to clear the blockage. Then, a stent is inserted into the artery, and a second balloon expands the stent to keep the newly cleared blood vessel wide open.
"The newest stents are coated with drugs to prevent tissue buildup within the arteries, which can create fresh blockages after the stent is in place."
However, the drug-eluding stent hay-day looks like it may be short lived. The results of studies revealed over the past several months set off alarm bells among heart specialists leading many to say they will return to the use of bare-metal stents.
The studies including the BASKET-LATE study, presented at the March 2006 American College of Cardiology Scientific Sessions in Atlanta, and most recently, the Camenzind meta-analysis presented at the September 2006 European Society of Cardiology Annual Meeting/World Congress of Cardiology Meeting in Barcelona, Spain.
The results of two Swiss meta-analyses of all available data from published trials of the Cypher, a sirolimus-eluting stent, and Taxus, a paclitaxel-eluding stent, reported at the meeting in Barcelona, found not only an increased risk of late mortality and non-fatal myocardial infarction with the Cypher stent, but also an apparent increase in all cause mortality. One of the meta-analyses showed a rise in non-cardiac deaths, from cancer, sepsis and stroke. They also found a slight increase in events with the Taxus stent.
The researchers found that drug-coated stents raise the risk of fatal blood clots and said the danger is greatest for patients with J&J's Cypher, who face a 38% higher risk of adverse events.
For people who develop a clot, experts say, it can be a matter of life and death because a clot inside the stent can stop the blood flow to the heart itself.
In the BASKET trial, researchers compared outcomes among 264 patients randomized to Cypher, 281 to Taxus, and 281 patients to a bare-metal stent, who were treated from May 2003 through May 2004, at University Hospital of Basel, Switzerland and were followed for 18 months.
The average age of the patients was 64 and forty-two percent had stable angina, 36% had unstable coronary syndromes, and 21% had acute MI and the analysis was based on data from patients who survived the first six months after stenting.
At 18 months, the rate of death or myocardial infarction was 8.4% for patients with drug-eluting stents and 7.5% for bare metal stents, but the study found a significantly higher rate of non-infarct target vessel revascularization for patients who received bare-metal stents compared with drug-eluting stents, specifically 11.6% versus 7.5%.
As a result, there was no statically significant difference in the overall major adverse cardiac event rate at 18 months, 15.8% for drug-eluting stents and 18.9% for bare-metal stents.
Patients who had treatment on larger vessels had no significant benefit from drug-eluting stents and possibly even a small late harm, the study found.
The take home message is clear, said Christoph Kaiser, MD of University Hospital Basel in Switzerland in MedPage Today on September 4, 2006, "Drug-eluting stents should be reserved for use in small vessels or bypass grafts because it is here that they have demonstrated a benefit."
Currently, drug-coated stents are used in more than 90% of procedures in rich countries like the US and Switzerland. But some cardiologists now say they will be much more cautious about their use. "It raises the flag of caution over the indiscriminate use of first-generation, drug-eluting stents and reminds us that we should stick with tested indications and not over-extend this to any patient," Dr Gabriel Steg, of Hospital Bichat-Claude Bernard in Paris, co-author of a Swiss meta-analysis, told reporters in Barcelona.
At one press conference, Salim Yusuf, MD, a professor of medicine and director of cardiology at McMaster University in Hamilton, Ontario, said that he plans to ask interventional cardiologists at his hospital to re-evaluate their use of drug-eluting stents so that they are used "in a limited way" until more data are available to determine whether the stents are "a panacea - as many of our patients and residents believe - or an expensive placebo, or - as I suspect - a Trojan horse."
Dr Yusuf says the stents may be more of a Trojan horse, carrying hidden long-term danger in the guise of a useful therapy to avoid restenosis. As it is now, Dr Yusuf characterized the widespread use of drug eluting stents as "madness" and said that coronary interventions should not be used to treat stable angina, unless it has "failed to respond to full and exhaustive medical therapy, something that is never done."
He is calling for the creation of a panel of interventional and non-interventional cardiologists, health economists, and government agencies to "re-evaluate the real role of stenting" in coronary disease and says the panel should exclude industry representatives.
During his presentation at the Barcelona conference, Dr Robert Harrington, of Duke in Durham, NC, warned the audience about the need to go slowly and evaluate the long term outcomes of the drug coated stents already implanted all over the world. "In days of balloon angioplasty, we worried about thrombus formation for 12 to 24 hours, and when bare metal stents were introduced, we worried for seven to 14 days," he advised.
But now the worry with drug-eluting stents, he pointed out, may "be extended to years."
Co-author of one of the meta-analysis, Dr Philippe Steg, MD, of Hospitalier Bichat-Claude-Bernard in Paris, likened the long term drug-eluting stent studies to long term data on Vioxx, which was viewed as a superior pain relieve treatment until long term studies found that the drug drastically increased the risk of heart attack and stroke.
The increased risk with Vioxx was small, but the drug was used by tens of millions of consumers before the risk became known. The same applies to drug-eluding stents. According to MedPage Today on September 5, 2006, an estimated 6 million drug eluting stents have been implanted, which means even a small percentage of problems can add up to a large number of patients.
"This is a classic kind of thing," said Dr David Brown, chief of cardiovascular medicine at Stony Brook University Medical Center, in Newsday on September 13, 2006, "every time we have a technological breakthrough, we invent a new disease along with it."
"In this case," he said, "it's late-stage thrombosis."
The September 14, 2006, New England Journal of Medicine, published 2 studies that found drug eluding stents offer modest benefits, if any, over bare-metal stents.
In one trial, researchers compared the Taxus to bare-metal stents, looking at their effectiveness in warding off cardiac death, recurrent heart attack or vessel re-closure. A total of 619 patients, who received a stent after a heart attack, were included in the study.
The researchers found no statistically significant difference in the rate of "serious adverse cardiac events" between the two groups during a one-year follow-up.
After one year, 8.8% of Taxus patients experienced an adverse event, compared with 12.8% of the bare-metal patients. Slightly fewer Taxus patients died from cardiac causes, had a reclogging, or needed another intervention, but blood clot rates were similar in both groups.
The second study compared the 8-month outcomes of 712 heart attack patients who were implanted with either the Cypher or a bare-metal stent.
In this study, time reductions in risk did reach statistical significance, with 7.3% of Cypher patients having a target-vessel failure, defined as a related death, complete reclogging, or need to reclear the vessel, compared with 14.3% of those given a bare metal stent.
However, the significant difference, the study said, was caused by a need for another surgery, as deaths and complete recloggings and blood clots were even in both groups, but patients with the Cypher needed their treated blood vessels unblocked after a year.
Another factor that must be considered in any risk benefit debate, is that according to the September 18, 2006 Boston Globe, "stents cannot be removed once they are implanted, making them a permanent fixture in coronary arteries."
As researchers tracked patients over time, they found clots forming more than a month, and sometimes a year or more after the implant. "With bare-metal stents, such late clotting is almost unknown," according to the Globe.
This past summer, Boston Scientific conducted its own an analysis of the company's drug eluding stent trials and acknowledged publicly that Cypher patients were marginally more likely to get a clot than patients with bare-metal stents.
J&J claims to monitor the long-term effects of its stents, and says that in 1,800 patients, five developed late clots, whereas none of the bare-metal stent patients had clots.
However, experts point out that the device maker's only track patients with fairly routine problems in their arteries but that in real-world practice, surgeons use drug-coated stents in many more complex cases.
In extreme situations, the Boston Globe says, doctors have implanted a dozen or more stents, or have completely lined a coronary artery with stents, a tactic called the "full metal jacket."
Experts say the more metal put in, the greater the risk.
Moreover, the number of cases of clotting problems may not be as small as experts predict. According to the September 18, 2006 Boston Globe, American doctors are starting to track their own patients and the Washington Hospital Center in Washington DC, looked at 3,000 patients and found 8 cases of late clotting.
In California, the Globe says, the Kaiser Permanente healthcare system is now launching a review of all its stent patients, though cardiologist Calvin Weisberger, who initiated the project but says a lack of funding will make the process slow.
"We don't have Boston Scientific or Johnson & Johnson paying for this study - they certainly won't pay for something that could show we should be buying less of their product," he told the Globe.
With drug-eluting stents, experts say, the increased adverse event rate is particularly alarming because the condition that the stent is used to prevent is a common but relatively benign process, while stent thrombosis is "a rare but life-threatening disease," according to Dr Steg.
Dr Steven Nissen, head of cardiovascular medicine at the Cleveland Clinic, called the new findings "potentially explosive."
He says there was already a modest shift back to bare metal stents in the US and predicts more doctors would take a conservative approach, pending definitive safety data. "If there's a suspicion, why take the risk?" Dr Nissen told Reuters News.
"If this is true," he advised, "I would recommend more selective use of drug-eluting stents and I would recommend consideration for longer-term use of dual anti-platelet (blood-thinning) agents."
Critics say the bad news about stent thrombosis is great news for Plavix maker Bristol Myers Squib. Along with Dr Nissen, Dr Yusuf also says there may be a need to continue dual antiplatelet therapy of aspirin plus Plavix in drug-eluting stent patients beyond the one year mark, and possibly for life.
Plavix is already a real moneymaker for Bristol-Myers, selling for about $4 a pill in the US. According to a February 27, 2006, article in Forbes.com, based on numbers obtained from IMS Health, a healthcare information tracking firm, the top 20 drugs in the US in 2005 included Plavix in the number 6 position with sales of $3.5 billion.
On July 18, 2006, the New York Times, reported that Bristol-Myers had already see a double-digit sales increase for Plavix in the US this year, up 26% to $850 million.
In addition to its extra costs, Plavix is not without its own serious side effects. A study published in the January 20, 2005, New England Journal of Medicine, found patients taking Plavix experienced more than 12 times as many ulcers as patients who received aspirin plus a heartburn pill.
The study treated 320 patients whose ulcers had healed and gave Plavix to half of the patients and aspirin plus Nexium, a heartburn pill to the other half.
The results showed 13 of the patients taking Plavix experienced renewed ulcer bleeding during the year while just one of the patients taking aspirin and Nexium had an ulcer bleed.
Medical experts also point out that Plavix is a long-lasting drug with no readily available antidote, which means once a patient takes it, their platelets are pretty much out of commission for about 7-10 days, the time it takes for the body to get rid of the old platelets and make new ones.
That is why some surgeons say they do not like the drug. One surgeon described performing a major emergency operation on a patient taking Plavix as either a "death-defying high wire act above Niagara Falls, or a death-producing disaster."
Critic note the added expense and risks of Plavix for all the people who would not ordinarily need the drug, and who may not even need it now if no clotting occurred, but who have to take it as a precautionary measure.
A precautionary measure that may in itself be dangerous or as useless as the drug-eluding stents. A study published in the April 20, 2006, New England Journal of Medicine, led by Dr Eric Topol and Dr Deepak Bhatt of the Cleveland Clinic, found that the combination of aspirin and Plavix not only did not help most patients with heart disease, it almost doubled the risk of death, heart attack or stroke for those with no clogged arteries but with conditions like high blood pressure and high cholesterol.
The researchers gave one group of patients a daily dose of aspirin plus Plavix, and another group was given aspirin plus a placebo. After 28 months the researchers found that adding Plavix made little difference to the group as a whole other than reducing hospitalizations slightly.
But for the 20% of the trial subjects with no signs of heart disease, the rate of heart related deaths went from 2.2% of those patients on aspirin alone to 3.9% of those who added Plavix.
The only patients even modestly helped, the study found, were those with established heart disease but even their risk of heart attack, stroke or death was about 7% versus 8% with aspirin alone.
In addition to finding no significant benefit with the combination, Plavix plus aspirin for patients with multiple risk factors was associated with increased risk for moderate and serious bleeding, the researchers reported. The analysis of adverse events showed that patients taking the combination of drugs had a severe bleeding rate of 1.7 %, compared to 1.3% for the aspirin only group.
And finally, there is no guarantee that a life-long regimen of Plavix plus aspirin will solve the problem. The data from Berne and Rotterdam-registries that include 3,875 Cypher patients and 4,271 patients implanted with Taxus stents found that 23% of late thrombosis occurred in patients who were already on dual antiplatelet therapy.
In one of two meta-analyses reported, patients treated with Cypher had significantly greater mortality and non-fatal myocardial infarctions at three years than did patients with bare-metal stents.
Dr Sidney Smith Jr, of the University of North Carolina at Chapel Hill, and chairman of the American College of Cardiology/American Heart Association Percutaneous Coronary Intervention Guideline Committee, points out that the guidelines already recommend that dual antiplatelet therapy be continued for a year in patients who have no excess bleeding risk and says there is no evidence that extending the aspirin plus Plavix therapy beyond a year will reduce the late thrombosis risk.
For its part, at its usual slow as molasses pace, on September 18, 2006, the FDA said it plans to convene a public panel meeting of outside scientific experts in the near future to assist in a review of all the data and make recommendations about what actions may be appropriate, such as possible labeling changes or additional studies.