Dementia relief, with a huge side effect
The off-label use of some drugs is helping elderly patients, but may be killing thousands.
Two years ago, federal regulators sounded a dire warning: Elderly people with dementia who take drugs like Seroquel, Risperdal and Zyprexa could suffer the ultimate side effect.
They could die.
Yet today, about one in four nursing home residents still take these antipsychotic drugs. Sales to the elderly continue to rise, generating a total of $13-billion in revenues for their manufacturers this year.
The disconnect between government warnings about the increased risk of death and physician prescribing practices led a prominent Food and Drug Administration safety expert to make a stunning estimate.
Dr. David Graham, who had blown the whistle on the dangers of Vioxx, was back before a congressional panel in February. He testified that Zyprexa and other antipsychotics kill about 15,000 nursing home residents each year.
His pronouncement did not spark any followup investigations; it did not prompt government-sponsored research for safer alternatives. Instead, there was resounding silence.
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Why was there no outrage?
Barbara Hengstebeck, executive director of the Tallahassee-based Coalition to Protect America's Elders, thinks she knows.
"A lot of people feel like the elderly in nursing homes are expendable," she said. "They're old anyway, they have dementia anyway, they're of no value to society. So what's the big deal? That's a sad commentary."
But people who deal with dementia patients say it's a devil's dilemma. Yes, the drug might kill them. Then again, it might make their remaining days easier - not only for the patients but for those around them.
In nursing homes, where resources are strained and staff overworked, medication that can prevent residents from hurting themselves or others is often the only option, regardless of the risks.
"There are time restraints, financial restraints and limited resources," said Dr. Fadi Saba, a St. Petersburg internist who sees patients at several local nursing homes. "So we go to pharmaceutical intervention."
Psychosis and behavioral problems associated with dementia are the No. 1 reason people end up in nursing homes. If their behavior can be controlled with these drugs, sometimes they can stay home longer.
Robert Wager, an 89-year-old St. Pete Beach resident, was diagnosed three years ago with Alzheimer's disease, one of the leading causes of dementia. He would erupt into eye-popping rages over nothing.
"It would come out of the blue and all hell would break loose," his wife, Leora, said of the incidents, one triggered by dirty measuring spoons. "It was to the point where I was absolutely terrified."
Two years ago, Wager's doctor, David LeVine, recommended 2.5 mg of Zyprexa at bedtime. It has made all the difference.
"Now he's a pussycat," Leora said. "It's not like he's in a stupor. He's still active, walking the dog and pulling weeds. If he weren't on Zyprexa, he'd probably have to go somewhere."
LeVine, a family practice doctor and medical director at Menorah Manor in St. Petersburg, said he focuses on improving a terminal patient's quality of life.
"If it means speeding death slightly, there's some risk/benefit there," he said. "If it means being able to keep them in their homes longer, it's the quality of the time that they're here. That's why we keep prescribing these drugs."
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Seroquel, Zyprexa and Risperdal are the bestselling brands in a class of drugs called atypical antipsychotics. Approved by the FDA during the 1990s, they were hailed as a major improvement over earlier antipsychotics, known as typicals.
Those drugs, including Haldol and Thorazine, could turn patients into zombies and cause severe shakes and involuntary facial tics. With atypicals, those side effects were far less likely.
The FDA approved atypicals only for bipolar disorder and schizophrenia, diseases that affect just 1 percent of all adults. But doctors can prescribe drugs for unapproved, "off-label" uses. They quickly discovered that atypicals seemed to be effective in dealing with behavioral problems associated with dementia in the elderly.
"They calm a person down," Saba said. "And when you find something that works, you stick with it."
Eager to boost sales, drugmakers began targeting family practice doctors and nursing homes. Pharmaceutical reps should have been hamstrung: By law, drug companies are allowed to promote their products for FDA-approved uses only. And few elderly suffer from schizophrenia and bipolar disorder.
But legal restrictions only meant drug reps were smoother in their sales spiels.
Doctors like Amanda Smith at the Suncoast Alzheimer's and Gerontology Center in Tampa say that the reps know just how to avoid crossing the line. "A lot of this is ridiculous charade," said Smith, who said sales reps never specifically claimed their products worked for dementia.
"They know full well that we don't see anyone with schizophrenia or bipolar disorder. But they figure if people are going to get something an atypical, they might as well get their product."
The extent of the charade at Eli Lilly & Co. can be seen in confidential marketing documents that became public late last year in response to thousands of lawsuits that claimed Zyprexa led to weight gain and diabetes in younger patients.
Buried in those documents are details abouthow the company created a 280-person "long-term care" sales force and internal memos that referred to nursing homes and assisted living facilities as an "opportunistic market."
Lilly also coached sales reps to approach family doctors, who would normally refer patients with schizophrenia to psychiatrists. During a "Viva Zyprexa" sales meeting in March 2001, company executives urged reps to build sales by using an imaginary patient dubbed "Martha."
Described as a widow who lives alone and is increasingly agitated, confused and unable to sleep, Martha was portrayed as an ideal candidate for Zyprexa.
"What's the first thing you notice about Martha?" Mike Bandick, Zyprexa's brand manager, asked the sales reps. "She's old!"
Martha's age "reinforces Zyprexa as a nursing home drug," Bandick said, but her symptoms also are commonly seen by family doctors.
"Agitation, tension, anger, hostility all show up in primary care in a variety of packages," he said.
Using the generic name for Zyprexa, Bandick told sales reps, "Olanzapine is the molecule that keeps on giving."
Marni Lemons, a Lilly spokeswoman, defended the company's sales to primary care physicians, saying they often deal with serious mental illness.
"We believe that it is absolutely appropriate to discuss Zyprexa and its indicated uses with primary care physicians in the interest of meeting a critical medical need," she said.
As it turned out, it was partly Lilly's desire to legitimize Zyprexa's use for dementia that led to the FDA's black-box warning. Lilly halted a study of the drug in the elderly population after it showed increased risk of death and strokes.
The FDA then analyzed data from 17 studies of four atypicals and found that the rate of death for elderly dementia patients treated with an atypical was 1.6 to 1.7 times that of a placebo. Most common causes of death were heart failure or pneumonia.
The FDA and researchers are not sure how atypicals increase the risk of death in the elderly, though they've long been aware of dangers with antipsychotics.
Since 1987, when medications like Haldol were widely used to control behavior, federal rules have required nursing homes to keep close tabs on the use of what are called "chemical restraints."
No physician in Florida prescribed more Zyprexa to elderly Medicaid patients last year than Dr. Laurence Petty, according to state data. A geriatrician for 17 years, his practice involves visiting more than 30 nursing homes in the Tampa Bay area.
Petty said the FDA's black-box warning on atypicals had no impact on his prescribing practices. Nor has the demand for these drugs lessened, he said, despite him spelling out the potentially fatal risk to patients and their relatives.
"I have family members asking me to put their moms and dads on something," he said. "It's hard to visit them in the nursing homes when they're screaming."
Ginny Hoar, consulting pharmacist at St. Petersburg's Bon Secours-Maria Manor, said she often suggests patients be weaned off atypicals, especially if staffers detect side effects like excessive drowsiness or falling.
Hoar recently found that 60 of 260 patients at Maria Manor were on atypicals. She recommended discontinuing the treatment for just two of them.
"The FDA can put out a black-box warning, but that doesn't mean the disruptive behavior just goes away," she said. "You have to consider the risks if we don't use the medicine. But it would be nice if there were other options."
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There are other options, but they take time, money and effort.
At the Cobble Hill Health Center in Brooklyn, Dr. Louis Mudannayake decided to try to change the thinking at his 400-bed nursing home.
Ignoring naysayers and the doomsday predictions of senior nurses, 18 months ago he put together a team of pharmacists, social workers and recreational therapists to review every atypical prescription.
If a new roommate caused agitation, room assignments were changed. If a new aide was hit while dressing a patient, the aide was given special training on that patient's preferences and routine.
Though the nursing home's resources were initially stretched, Mudannayake said the quality of patients' lives improved. "Ultimately, I'm convinced financial expenditures will be diminished, because it's easier to manage a patient who is calm," he said.
"We instituted a cultural change. That's what's required to bring the numbers down," said Mudannayake, who said psychiatric hospitalizations did not increase as medication dropped.
"You'll always have doctors say there's nothing else to use but atypicals, and I agree there are a small minority of patients where you need to use these drugs. But not in the numbers we are using them."
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Despite an undeniable and growing need for safer medications to control dementia, drug companies have little incentive to develop such drugs when their existing products are still bringing in billions.
Though Lilly warned doctors in 2004 that Zyprexa can cause death in the elderly, last year the over-64 age group still accounted for more than 26 percent of the drug's total prescriptions. Zyprexa had $4.4-billion in sales last year.
"There's very high risk for trying to study new drugs in older patients because it's always more complicated," said Dr. Bruce Pollock, with the Rotman Research Institute at Baycrest in Toronto.
"But what good does it do if drug trials are only conducted in healthy, middle-aged people with only one condition? It's a disservice to the biggest consumers of pharmacy that we don't have adequate data."
About the drugs
What the FDA said: Based on results from 17 trials, the agency concluded in April 2005 that the death rate for patients on atypical antipsychotics was about 1.6 to 1.7 times higher for elderly patients with dementia than for those taking a placebo.
What's a black-box warning? So named because of the black border that surrounds it on the drug label, it's the FDA-required disclosure that a drug can have serious or life-threatening side effects.
What drugs got black-box warnings? Abilify, Zyprexa, Seroquel, Risperdal, Clozaril, Geodon and Symbyax (a combination atypical and antidepressant)
Top-selling atypicals: total 2006 sales, percent of Rx to elderly
Seroquel: $3.4-billion, 19 percent to patients over 64
Risperdal: $4.2-billion, 19.7 percent to patients over 64
Zyprexa: $4.4-billion, 26.6 percent to patients over 64
Source: Company reports, Verispan'What are some of the other red flags we should be watching for?'
Testifying at a congressional hearing, Dr. David Graham, a prominent FDA drug safety expert, was asked if he had issues with any medications already on the market.
"I would pay careful attention to antipsychotic medications. ... The problem with these drugs are that we know that they are being used extensively off-label in nursing homes to sedate elderly patients with dementia and other types of disorders. ...
"But the fact is, is that it increases mortality perhaps by 100 percent. It doubles mortality. So I did a back-of-the-envelope calculation on this and you have probably got 15,000 elderly people in nursing homes dying each year from the off-label use of antipsychotic medications. ...