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April 7, 2004
Nominal Benefits Seen in Drugs for Alzheimer's
By DENISE GRADY
The drugs now available to treat the memory and thinking problems of Alzheimer's disease have not lived up to the public's high expectations for them and offer such modest benefits on average that many doctors are unsure about whether to prescribe them.
Although the drugs have their advocates, grateful for any sign of improvement, others express disappointment in light of earlier hopes that the drugs approved in the last decade would stop the disease or markedly slow it.
At a meeting in late March at Johns Hopkins University, doctors and other health professionals heard Alzheimer's researchers debate the usefulness of the drugs and the prospects of better treatments becoming available any time soon. Some researchers say it may be decades before real progress is made in reducing the toll of the disease.
When a frustrated doctor in the audience accused a panel of experts of evading the question of whether the drugs should be prescribed, the auditorium burst into applause.
One expert replied that there was just one chance in 10 that the drugs would have an effect and that patients should try them for six to eight weeks and then quit if there was no improvement. A second expert gave the drugs somewhat better odds of helping. A third said to try the drugs for six months. A fourth said, "The kind of evidence you want may not be available."
The moderator summed up, saying: "For us to tell you what to do, I think would be wrong. All you can do is look at your soul and do the best you can."
About 4.5 million Americans suffer from Alzheimer's disease, and many patients and their families see the five drugs now available to treat it as their only defense against its relentless destruction of the mind. Patients usually take one drug. Each costs about $120 a month. They are meant to aid thinking and memory, though they do not change the underlying course of the illness. A million Americans take them, at an overall cost of $1.2 billion a year.
"We don't want to raise expectations that the effects of these drugs are large," said Dr. Peter Whitehouse, a professor of neurology and bioethics at Case Western Reserve University.
And yet the medicines are all that doctors have to offer. Though researchers are trying to develop new treatments, no breakthrough is near, said Dr. Constantine G. Lyketsos, director of the Alzheimer's center at Johns Hopkins.
"The public thinks a cure is around the corner," Dr. Lyketsos said. But he said he did not expect any "realistic reduction in the huge number of cases for decades."
Clearly, the drugs can alter brain chemistry, and some studies show statistically significant improvements on tests that measure thinking and memory. But while a few extra points on a mental exam, or other changes obvious to a specialist, may be enough to get a drug approved by the Food and Drug Administration, they may not be enough to help a person with Alzheimer's dementia function in the real world.
"You can name 11 fruits in a minute instead of 10," said Dr. Thomas Finucane, a professor at Johns Hopkins and a geriatrician. "Is that worth 120 bucks a month?"
Dr. Finucane, the conference speaker who advocated a six-to-eight-week trial of the drugs, said that most of his patients tried Aricept, the leading drug, but that only 10 percent of them found it worth continuing.
"There is very limited efficacy in making the patient's life or the caregiver's life better," he said, noting that a professional group, the Academy of Neurology, had stopped short of recommending the drugs but had instead urged doctors to "consider" using them.
Four drugs — Aricept, Exelon, Reminyl and Tacrine — are approved to treat the symptoms of mild to moderate Alzheimer's. All raise levels of acetylcholine, a chemical that transmits nerve signals in the brain. A fifth drug, Namenda, which works on a different neurotransmitter, was approved last year for moderate to severe cases.
"In my opinion, in 10 years we'll be embarrassed by how much of this stuff we prescribed," Dr. Finucane said, adding that he thought hundreds of millions of dollars were being wasted on the drugs. But he also said he understood why patients and families wanted them.
"Alzheimer's disease is a slow-motion disaster," he said. "It's very hard to sit by and watch. There is an overwhelming desire to do something, even if it's to give a useless pill every day."
Dr. Steven T. DeKosky, chairman of neurology and director of an Alzheimer's research center at the University of Pittsburgh, said he took a very different approach, prescribing drugs for all his Alzheimer's patients unless they cannot tolerate them. He said that it took at least six months to tell whether the drugs were helping.
Dr. DeKosky said the "data are overwhelming" that the drugs help patients stay functional a bit longer. In addition, he said, family members often tell him that patients improve with the medicines, or at least seem to decline less steeply. From 7 to 10 percent, he said, have a noticeable, if temporary, improvement, which researchers call a "Lazarus effect."
"They are symptomatic, mildly effective medications," Dr. DeKosky said. "They are not the silver bullets to stop the disease or slow it down. They don't restore anybody's memory to what it was in the past."
The drugs can buy patients some time, blunting the deterioration for up to a year, Dr. DeKosky said.
"At this point, small victories are what we have to settle for," he said.
Researchers acknowledge that opinions diverge widely on the treatments. Dr. Jason Karlawish, a geriatrician at the University of Pennsylvania's Institute on Aging, said, "There is substantial controversy over the claim that current F.D.A.-approved treatments improve function or slow a patient's decline."
He blamed several factors for the controversy, including "the lack of widely understood and accepted measures to show improvement or slowing of decline, small effects on the few measures some experts agree are appropriate, and controversial and even outrageous approaches to analyzing the data to make the claim the drug slows a patient's decline."
Dr. Karlawish, Dr. Finucane and other researchers said they were particularly irked by a study published last July in The Journal of the American Geriatrics Society, claiming that Aricept could delay a patient's need for nursing-home care by nearly two years — something that would clearly matter to patients and families.
Pfizer, which makes Aricept, paid for the study and its scientists were among the article's authors. The critics said the study was flawed, and its data did not support the claim.
Letters criticizing the study, and the authors' rebuttal, are to be published in the May and June issues of the geriatrics journal.
The editor of the journal, Dr. Thomas Yoshikawa, declined by e-mail to discuss the details of the study but said that it had passed muster with journal editors and several outside experts. But he also noted that expert opinion was divided as to whether the drugs improve quality of life for patients or those caring for them.
An author of the study, Dr. David S. Geldmacher, a neurology professor at the University of Virginia, said, "I believe the data we report are accurate and the conclusions are appropriate."
In interviews, Alzheimer's patients and their relatives said they were pleased to have the drugs, and most thought they helped.
Cathleen McBride, 64, a retired guidance counselor and English teacher in Bridgewater, Mass., whose case of Alzheimer's was diagnosed two and half years ago, said she had been taking Aricept for almost two years.
"I'm holding my own," she said. She can no longer cook or drive, but she continues to read, do crossword puzzles and give public talks about Alzheimer's disease.
Asked if the drug made a difference, she said: "I can't say. It's hard to observe oneself in a situation like this."
Her husband, Owen, said, "There's no way to check it unless you stop and see if you fall through the floor."
Isabel Shipmon, a real estate agent in Middletown, N.Y., said that her mother, Luisa Cancel, took Aricept off and on for a few months at a time, for a total of about a year.
"It kept everything balanced for a minute," Ms. Shipmon said. "She seemed like she was a little bit more alert, held her thoughts a little longer, like it didn't progress. You have her for a second, and that's it."
Gradually the drug seemed to stop working, Ms. Shipmon said. Her mother is now in a nursing home.
Marie Heuer, a retired secretary in St. Louis, has been taking Aricept since learning she had Alzheimer's disease about four years ago at age 55.
The drug had an immediate effect, she said: "It was like a cloud being lifted. I'm very grateful we've gotten it."
Martha Daly, who lives with Ms. Heuer, said: "The progression slowed immediately. It was obvious to her friends and certainly to her family."
Once a patient starts taking a drug, even if there is no obvious improvement, many doctors and family members hesitate to stop, because they figure the drug is doing no harm and think it may at least be stopping the patient from getting worse. And they fear that quitting may lead to a sharp decline.
Emerson Moran, a writer in Palm Beach Gardens, Fla., said his wife, Pat, 64, had been taking Aricept for about five years. He said it seemed to make her more alert and may have helped her regain a bit of her ability to read, but that the effects lasted no more than a year, which was about what doctors told the couple they might expect.
He is still giving his wife the pills. "Why not?" he said. "Our physicians throughout have just recommended keeping her on it. My guess is that they don't know anything more than we do."
Correction: April 9, 2004, Friday
A front-page article on Wednesday about the usefulness of drugs prescribed for Alzheimer's disease misidentified the manufacturer of Aricept. It is made by the Eisai Company. Pfizer markets it in the United States along with Eisai.
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