2-Part Series Feds Investigate Profits From Off-Label Heart Stent Procedures

Evelyn Pringle May 2007

The stenting for profit industry may soon be history. On March 1, 2007, the chairman of the US House Oversight and Government Reform Committee, Henry Waxman (D-CA), ordered Johnson & Johnson and Boston Scientific to turn over documents as part of an investigation into the off-label marketing of drug-eluting stents.

Boston’s Taxus, and J&J’s Cypher are the only DES stents FDA approved for sale in the US, but they were approved for limited indications because the studies submitted to support their approval only tested the stents in patients with single, smaller artery blockages, according to the December 8, 2006 Science Daily.

“But doctors quickly started using them,” Science reports, “in patients with blockages in multiple vessels and in those with larger blockages or co-existing diseases like diabetes.”

Stents are tiny wire-mesh tubes inserted in arteries to keep them open after angioplasty, a procedure in which a balloon is threaded through a vessel in the groin to a blocked artery and then inflated to unclog the artery to restore blood flow to the heart.

The use of stents became popular because the procedure was promoted as being safer and cheaper then heart bypass surgery in which an entire section of a diseased artery is replaced with a vessel taken from elsewhere in the body.

The drug coating on the new expensive stents was a big selling point in convincing doctors to quit using the older bare-metal stents, because the drugs were supposed to reduce the need for repeat procedures by releasing medication to prevent restenosis where scar tissue forms and causes the artery to close up again.

But DES stenting is so profitable that the majority of patients receiving the stents will not benefit at all. At a cost of $10,000 to $38,000, as many as 85% of the procedures are non-emergency and are being performed on people with only partially blocked arteries for the relief of recurrent chest pain, according to March 23, 2007 Associated Press.

The first DES was approved in April 2003, and by December 2006, at a hearing on the “Prospective on Drug‑eluting Stents: Balancing Risks and Benefits,” an FDA advisory panel reported that 3 out of 5 procedures were for unapproved uses and DES patients were developing stent-thrombosis, or blood clots, occurring most often in patients when the devices were used off-label.

While testifying at the hearing, Dr Sanjay Kaul told the panel that bare-metal stents were hardly used anymore. “The current drug‑eluting stent utilization rate,” he said, “is about 80 percent, and we have learned that nearly 60 percent of it is off-label.”

“We’ve also learned from the off-label use,” he informed the panel, “that the risk of stent thrombosis is higher, 2 to 3 percent, and in some subsets, like insulin-requiring diabetics, as high as 5 to 6 percent.”

As a result of the massive off-label use of DES, by 2005, the device accounted for 43% of total sales for Boston and 52% for J&J, according to Bloomberg on December 4, 2006. By 2006, sales figures show the new stent was a $2 billion seller for Boston.

The stents have been implanted in more than 6 million people worldwide, in what market analysts are calling a modern day record for a new device. In the January/February 2006 issue, Medical Device Link reported that about 1.5 million patients in the US were implanted with stents in 2005.

Yet by end of 2006, Forbes was reporting a study that found that angioplasty and stents did not help patients when used within a few days after a heart attack occurred which “could mean 50,000 such procedures were done unnecessarily every year,” Forbes said on December 13, 2006.

And new reports continue show that these unnecessary procedures are extremely costly in more ways than one. On May 14, 2007, Medical News Today reported that 2 studies in the Journal of the American Medical Association found the off-label and untested use of DES is common in US practice, and “ischemic complication rates are higher among patients receiving drug-coated stents for off-label indications.”

In one study, 10.9% of patients who got stents for unapproved uses died, had a heart attack, or needed further treatment to clear the artery, compared with 5% of patients who received the devices during on-label procedures. After a year, the study found, the number of complications in off-label patients rose to 17.5% compared to 8.9%.

According to Darshak Sanghavi, a pediatric cardiologist and assistant professor of pediatrics at the University of Massachusetts Medical School, in Slate Magazine on May 8, 2007, “we’ve wasted a lot of time and money on cardiac angioplasty that does no good.”

“Time and time again, he wrote, “studies repeatedly show that opening blocked arteries to prevent heart attacks in people with exercise-induced chest pain or stable blockages is, quite simply, pointless.”

“Essentially no clinical trial,” he says, “shows that balloon angioplasty or stenting partially blocked coronary arteries prevents heart attacks, saves lives, or reduces the risk of other complications like strokes.”

The bottom actually started falling out on the DES stenting for profit industry in late 2005, when reports began to emerge showing patients were developing serious health problems. Unbeknownst to the public, within 6 months of the approval of the first DES, the FDA had already identified 50 cases of allergic reactions associated with new stents.

On January 3, 2006, the Journal of the American College of Cardiology reported a study that found a number of patients had developed serious allergic reactions. A review of the FDA’s adverse event database since the first DES was approved through December 2004, initiated by cardiologists at the Health Science Center, identified 17 allergic reactions that were classified as probably or certainly caused by the stent, and 4 resulted in death.

Symptoms included rash, difficulty breathing, hives, itching and fevers and the study concluded that the coating on the stent was the likely cause rather than the drugs released by the device, according to a December 20, 2005 Health Science Center news release.

“The patients in question are not allergic to the stent itself, but to the polymer coating the metal used to hold the drugs for 30-day release,” said the report’s lead author, Dr Marc Feldman, associate professor of medicine at the Center and associate director of cardiac catheterization laboratories at its teaching University Hospital.

During 2006, reports that patients were developing stent-thrombosis started popping up. On October 11, 2006, the American College of Cardiology posted an editorial on the internet by Dr Sanjay Kaul, director of the cardiology fellowship training program at Cedars-Sinai Medical Center in Los Angeles and a colleague, that warned that blood clots in drug-coated stents may be causing an extra 2,160 deaths in the US alone each year.

On October 23, 2006, Bloomberg reported that 2.9% of DES patients could develop stent-thrombosis within 3 years and because 4 million people had already received the new stents, “clotting related to drug-coated devices may have caused as many as 20,000 heart attacks and 10,000 deaths worldwide.”

A November 29, 2006 analysis by the Cleveland Clinic Foundation found that the risk of developing blood-clots was increased as much as 5-fold in patients who receive drug-coated stents compared to patients implanted with the old bare-metal stents.

In December 2006, the FDA panel also sought to determine whether DES patients could forestall the occurrence of stent-thrombosis by taking the anti-clotting drug Plavix and aspirin for a year or more.

With the drug costing about $4 per day, the increased use of DES had already provided a goldmine for Plavix marketers Bristol-Myers Squibb and Sanofi-Aventis because every patient was instructed to take the drug for 3 to 6 months. By 2005, Plavix had become the world’s second-best-selling prescription medication.

But the use of Plavix creates problems of its own. At the FDA hearing, Dr Ron Waksman, who presented data from the Contemporary Registries of the Washington Hospital Center, told the panel, “we know that there is a price to prolong Plavix, and this has been given us from three randomized studies in which Plavix was compared to aspirin alone.”

He noted that all 3 studies showed there was excessive bleeding with Plavix.

He also told the panel that overall, compliance with taking Plavix at the time the stent thrombosis occurred in patients was actually fairly high. Although 30.4% of patients were off Plavix, he said, 60% of patients were still on Plavix.

Furthermore, Dr Waksman informed the committee, “platelet therapy beyond 6 months is not proven yet to be prohibitive to late stent thrombosis.”

Medical experts also say taking Plavix is not recommended unless absolutely necessary because severe bleeding can occur if a patient needs sudden surgery. And stopping Plavix will not help because it takes about a week for platelets to get back to normal with the proper clotting effect which makes any surgery a life-threatening event.

In the end, the FDA panel recommended that the DES should carry warnings that the devices may increase the risk of sudden heart attack or death and said patients may have to take Plavix for the rest of their lives.

So here once again, a new product that supposedly showed few risks in company sponsored trials with a small number of patients, actually causes serious health problems that went undetected until after the device was implanted in millions of people in large part due to the massive off label marketing of the device the minute it was FDA approved.

But in this instance, the off-label sale of the DES has resulted in a public health crisis because the adverse events are lethal. A clot inside a stent can instantly cut off the blood supply to the heart and patients can not have the device removed because tissue grows over the stent once it is placed in the artery. And taking Plavix for life, if it even helps, creates another life-long health threat.

The fact is, there is no medical solution to this problem and the millions of patients implanted with the stents who are lucky enough not to experience an adverse event will still have to endure a lifetime of day to day worry and dread.

Feds Investigate Profits From Off-Label Stent Procedures – Part II

In addition to the federal investigations into the off-label marketing of drug eluting stent by Boston Scientific and Johnson & Johnson, on May 10, 2007, Rep Maurice Hinchey (D-NY), who serves on the House Appropriations Subcommittee, announced the introduction of the FDA reform bill which addresses the issue of doctors using products for unapproved uses, which usually occurs without the patient’s knowledge or consent.

If a doctor does not inform a patient that the FDA has not approved the use of a device or procedure, medical experts say, the patient cannot give meaningful consent because the potential problems that can result from the off-label use must be explained so that the patient can weigh the risks and benefits to determine whether to consent to the treatment.

Medical professionals point out that if a doctor wants to use a treatment that is not FDA approved because of a true belief that a certain patient would benefit from a specific treatment more than from others that are FDA approved, the doctor would not hesitate to explain the reasoning to the patient.

The FDA Improvement Act reform bill introduced by Rep Hinchey would require doctors to inform patients when a product is used off-label and also provide more resources to the FDA to go after companies that promote off-label use of their products despite the fact that doing so is illegal.

In recent months, lawmakers have made it clear that investigation of the stenting for profit industry is a top priority and will include not only the device makers, but also the doctors and medical facilities performing the procedures.

Being Congress oversees the spending by public programs like Medicare and Medicaid, lawmakers would have to be blind not to notice the obscene rise in profits. According to the May 17, 2007 Wall Street Journal, “Americans spent at least $14 billion on coronary-stent procedures last year, including surgical and hospital fees.”

Stenting doctors are very well paid. The median salary for invasive cardiologists who perform the procedures is roughly half-a-million dollars a year, says Darshak Sanghavi, a pediatric cardiologist and assistant professor of pediatrics at the University of Massachusetts Medical School, in Slate Magazine on May 8, 2007.

However, doctors and medical facilities may now be reevaluating the benefits of continued off-label stenting since law enforcement officials released information this month from an investigation by the FBI and the US Department of Health and Human Services of a cardiologist at a facility in Maryland that found 25 unnecessary stents implanted in patients in 2006 alone, with the majority billed to Medicare.

The bare-metal stenting procedure was originally marketed as a cheaper alternative to heart bypass surgery, but since the arrival of the DES, that claim is bogus. On February 25, 2007, the New York Times quoted the American College of Cardiology in reporting that the average cost of the DES procedure has risen to about $30,000, or almost equal to the price of open heart surgery for patients with multiple blockages.

The DES were promoted as being safer than bare-metal stents, but on March 8, 2007, the New England Journal of Medicine published an analysis of 4 studies that compared the DES and bare-metal stents with 4 years of follow-up, and found no significant differences in the rates of death, myocardial infarction, or stent thrombosis with the survival rate in the DES group at 93.3%, and 94.6% in the bare-metal group.

In December 2006, the FDA’s Circulatory System Devices Advisory Committee held a hearing to review data on the outcome of DES stenting when they were implanted according to their label compared to when they were used off-label. Dr Ron Waksman, of the Washington Hospital Center, told the panel the rate of stent thrombosis almost doubled in patients with off-label use versus on-label use at 30 days and at 12 months.

He also said, “when we look at on-label and at off-label, the drug‑eluting stents are more thrombogenic than bare-metal stents.”

With both on-label and off-label use, he informed the panel, over time, “late stent thrombosis is seen more in the DES versus the bare-metal stents.”

Dr Waksman said that careful patient selection for DES is mandatory, and “off-label use should be reconsidered or restricted.”

Diabetic patients with multi vessel disease should always be referred for bypass surgery, he added. DES should be contraindicated, he said, “for patients with poor compliance or allergic to Plavix or aspirin and need for upcoming surgery, and warning labeling should be considered for those when used off-label.”

But experts point out that some studies have shown little benefit from taking the anti-clotting, blood-thinning drug Plavix to prevent stent-thrombosis. In October 2006, Dr Alaide Chieffo, made a presentation at a Transcatheter Cardiovascular Therapeutics meeting and reported a study of 3,021 DES patients that found 9 out of 16 patients who had developed late stent-thrombosis were being treated with Plavix at the time.

At the FDA meeting, Dr Peter Smith of Duke University discounted the claims that stenting is safer or as effective as bypass surgery and warned of the importance of weighing the risks and benefits to patients treated with the different procedures.

He stressed that since the introduction of DES, too many patients in need of bypass surgery are instead receiving off-label stenting procedures. “A current perspective,” he said, “is that America’s number one killer is predominantly treated with percutaneous methodology that has not been demonstrated to provide a survival advantage.”

“And this is particularly important,” he advised, “for the treatment of multi vessel coronary disease where substantial quality of life and survival benefits have been conclusively demonstrated for bypass grafting.”

Dr Smith informed the panel of some of the outcomes reported in peer-reviewed published trials, the first a study of 14,000 patients, which demonstrated a significant survival advantage for bypass grafting compared to stenting in three vessel heart disease, he said.

The ROBUST New York State audited database, he reported, of 23,000 patients with three vessel disease published in the New England Journal of Medicine also showed a significant survival advantage for bypass grafting compared to stenting at 3 years.

Dr Smith explained that bypass grafting is more effective because it provides complete revascularization. While stenting treats the isolated blockage, grafting bypasses about two-thirds of the vessel where current and future blockage can occur.

In addition, he noted, bypass risks increase little with increasing coronary disease severity while risks with stenting appear to increase with each additional stent.

He also told the panel, “surprisingly, when we looked at the bare-metal stent era data, we saw point estimate trends favoring bypass grafting even for low and intermediate severity disease, and an extension of the significant advantage that bypass grafting provides compared to intervention for high severity coronary disease.”

Dr Smith said the introduction of the DES led to a tripling of the use of stenting for high severity coronary disease. “And for the first time,” he noted, “less than half the patients were initially offered coronary bypass grafting.”

“How can this happen,” he pointed out, “with the absolute survival advantage that I’ve shown you from these observational data on 40,000 patients showing that at 1 year, there’s a 2.3 percent advantage, absolute advantage in bypass grafting versus stenting; 4.3 percent at 3 years; 5.1 percent at 5 years.”

That means 1 out of every 20 patients, he said, who were treated with stenting would have survived if they had had bypass grafting. When you translate into real world application, assuming that drug‑eluting stents are equivalent to bare-metal stents for the mortality outcome, he advised, approximately 1.5 million drug‑eluting stents are implanted worldwide, 850,000 in the US.

Using data from the DEScover trial about stents per patient in the incidence of three vessel disease, he said, we estimate that 160,000 are with DES worldwide and 92,000 in the US.

Dr Smith informed the panel that this translates into a rate of premature death at 1 year to 3,800 patients worldwide, with 2,000 in the US, and 16,000 patients deaths at 3 years, with 9,000 in the US.

“Annualized,” he said, “this is 6,500 worldwide, 3,600 in the U.S.”

At the end of his presentation Dr Smith addressed previous claims made to the panel by the industry that off-label extension of DES was meeting “an unserved need.”

“We’re not certain whose unserved need that is,” he said, “but we’re fairly certain that it’s not the need of our patients.”

Another major selling point used by the stent makers has been to claim that bypass surgery is riskier. However, a study presented at the American Heart Association’s Annual Conference in April 2007, determined that the DES procedure and surgery have about the same risk for a major cardiac event based on an analysis of 799 DES patients and 799 bypass patients for outcomes in the first 30 days and during the following 3 years.

Lead author, Dr Wilson, a program director at St. Luke’s Episcopal Hospital and Texas Heart Institute, said in Science Daily on April 21, 2007, “We found that the likelihood of any complication in the hospital was the same whether you had a drug-eluting stent or bypass.”

“Five percent of drug-eluting stent patients,” he said, “had some major complication in the hospital, mostly heart attack, as opposed to about 3.8 percent of the patients who had bypass.” At 3 years, the study found, the death rate with bypass was 6.6% and 9% with drug-eluting stents.

The results of a study called COURAGE released in March 2007, may turn out to be the final nail in the coffin for Boston and J&J. The study involved over 2,000 patients who were treated for chronic, stable chest pain, and revealed that medication therapy alone reduced chest pain almost as well as when the drugs were combined with stenting.

Experts say the outcome is probably due to the fact that stenting only fixes one artery blockage at a time while drug treatment affects all arteries.

Many stable heart patients are conned into stenting because they believe that it will extend their lives and lower their risks for heart attack but according to the New York Times, the COURAGE study found that patients who received stents and drugs had the same life expectancy and same number of heart attacks as patients who received drugs only.

The study reported the rate of heart attack, stroke or death in patients who received stents was 20%, compared to 19.5% in patients who used drugs alone. At the end of 4.6 years, there were 211 deaths, or 19% among patients in the group who received stenting compared with to only 202 deaths, or 18.5% in the medication group.

“Our findings parallel those reported in recent trials,” said William Boden, chief of cardiology at Buffalo General and Millard Fillmore Hospitals.

“In the aggregate,” he told United Press International on March 26, 2007, “these studies … show that percutaneous coronary intervention — angioplasty plus stenting — has no effect in reducing major cardiovascular events.”

“There are hundreds of thousands of Americans who are currently getting stents placed who do not need it as initial therapy,” said Dr Raymond Gibbons, professor of medicine at the Mayo Medical School and president of the American Heart Association, to UPI.

In response to the study, on the March 28, 2007, WSJ Health Blog, Dr Andy Demajio wrote, “It has been distressing to see how interventional cardiologists have been happily stenting their patients to fatten their wallets.”

“This immoral practice should come to a stop,” he wrote. “My hope is that the COURAGE data may help payers take action against these doctors.”

It appears that doctors and hospital administrators are thinking twice about off-label DES stenting. On May 17, the Wall Street Journal reported that April marked the 10th consecutive month of share decline for DES, quoting the Millennium Research Group, a firm that surveys about 140 US hospitals, that put the percentage of stentings with a coated stent at 69.7%, down from almost 90% last in June 2006.

Until April doctors had largely replaced the more-expensive DES with older, bare-metal stents, the Journal said. “The new data,” it notes, “indicate that doctors and patients may be skipping stentings completely in favor of drug treatment.”

It sure looks that way according to Boston’s first quarter SEC filing, that reported worldwide sales of its DES had dropped to $468 million in the first quarter of 2007, down from $633 million during the first quarter of 2006.

The SEC filing also shows that J&J has plenty of other problems. For instance, the company is currently facing over 75 class action lawsuits and 1,100 individual lawsuits related to potentially defective defibrillators and pacemakers manufactured by Guidant, a company Boston acquired in April 2006.

J&J future isn’t looking too rosy either. Sales of the Cypher stent are down by more than 25%, according to the firm’s first quarter SEC filing and in addition to DES, J&J is currently under federal investigation over the marketing practices for several other products including the antipsychotic Risperdal, the anti-seizure medication Topamax, the heart-failure drug Natrecor, and paying kickbacks to doctors for using the firm’s orthopedic devices.

In March 2007, J&J received new subpoenas from US attorneys in Philadelphia, Boston and San Francisco pertaining to the investigations of the 3 drugs seeking information about corporate supervision and oversight of the subsidiaries that market the drugs including Janssen, Ortho-McNeil and Scios.

In addition, according to SEC filings, as of December 31, 2006, 100 lawsuits were pending against J&J related to the Charite artificial spinal disc, basically alleging that the company knew the disc was defective and boosted profits by marketing the device for off-label uses.

On May 10, 2007, the Wall Street Journal reported the filing of a lawsuit against J&J by two former salesmen with documents showing how the company “sought to boost sales of its blockbuster anti-anemia drug Procrit by offering contracts that fattened doctors’ profits and urging its salespeople to push higher-than-approved doses.”

This bit of news came shortly after federal lawmakers ordered J&J to cease all direct-to-consumer advertising and physician incentives for Procrit until the FDA could determine whether steps needed to be taken to protect the public following investigations that revealed the rampant off-label sale of the anemia drug was causing serious injuries and death among kidney and cancer patients.

Unfortunately, there is no way to medically reverse the stenting procedure and therefore, the millions of unsuspecting patients who received the DES face a life-time of every day worry because a blot clot lodged in a stent can cause a stroke or heart attack without any warning.

Legal experts are predicting that Boston and J&J will be swamped with lawsuits over the off-label marketing of DES, but say the defendants listed in the complaints will likely include the names of doctors and medical facilities that helped the device makers turn the stenting industry into a billion dollar baby.

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