If you are a man, you have a 1 in 6 chance of developing prostate cancer during your lifetime. The good news is that most men will die with prostate cancer, not of prostate cancer. The bad news is that some men will succumb to a virulent form of prostate cancer: even with surgery and/or radiation therapy, tens of thousands will develop metastatic disease. Initially, prostate cancer typically responds to hormonal therapy (the cancerous cells need male sex hormones to thrive so treatment that lowers the level of these hormones can hold the cancer at bay). But if it stops responding to hormonal treatment and new metastases develop, patients are in trouble. The cancer often travels to bones, causing pain and fractures. Sometimes it causes spinal cord compression, which can cause paralysis. According to the National Cancer Institute, about 32,000 men die of prostate cancer in the US every year.
When the Seattle-based biotech company Dendreon announced a radical new approach to the treatment of prostate cancer, the enthusiasm was palpable. As the company reports on its website, it is in the business of "transforming lives through the discovery, development, and commercialization of novel therapeutics." Its new strategy for prostate cancer is more like a vaccine than a drug and it involves a highly individualized approach rather than one-size-fits-all chemotherapy. Treatment entails drawing blood from a patient, removing the white blood cells, treating them in the laboratory to endow them with special anti-prostate cancer fighting properties, and then returning them to the patient. Three randomized controlled trials suggested that the new approach, called autologous cellular immunotherapy or sipuleucel-T (brand name Provenge) is effective with relatively modest side effects. The Food and Drug Administration approved sipuleucel-T in April, 2010. Now Medicare is trying to decide whether to pay for the therapy. Medicare has commissioned a "technology assessment" to evaluate the evidence that the treatment is effective; it has carefully reviewed all the available data, and it has assembled its advisory committee to make a recommendation. Much of the reason for all this scrutiny is cost: a full course of treatment (three infusions) is just under $100,000.
Since the FDA has found sipuleucel-T "safe and effective," isn't any restriction of usage by Medicare simply government interference in the practice of medicine? That's one way to spin Medicare's concern. It's certainly the view of the company that makes the sipuleucel-T system. But a sober assessment of the facts suggests the alleged benefits of immunotherapy may well be exaggerated: the system has only been shown to work in a small fraction of men with so-called castration-resistant metastatic prostate cancer; it does not prolong the length of time men go without progression of the disease; and its efficacy may depend on the use of conventional chemotherapy.
Which men stand to benefit from sipuleucel-T? To be eligible to participate in one of the 3 clinical trials of sipuleucel-T, men had to meet a whole slew of criteria. They had to have low testosterone levels (indicating their disease was progressive despite lowering of the male sex hormone), they had to be in generally good health (as indicated by independence in their daily activities), they couldn't be experiencing pain or taking narcotics for pain, and they couldn't have lung, liver, or brain metastases. In this carefully selected group, sipuleucel-T increased median survival by 4 months. We simply don't know whether the observed effectiveness of sipuleucel-T applies to men who do not meet these criteria.
What exactly does sipuleucel-T do? The first two clinical trials of sipuleucel-T concentrated on measuring the length of time before a patient's cancer progressed. The assumption was that even if the new treatment didn't cure prostate cancer-it didn't-it might extend quality of life, if not length of life, by offering patients a period in which they had no measurable tumor growth. Neither study found any such effect: the time until progression of the disease was in the range of 10-11 weeks with either sipuleucel-T or placebo. But surprisingly, median overall survival was 4 months longer with sipuleucel-T. A third study, undertaken after the first two and published in the New England Journal of Medicine, deliberately chose overall survival as the main outcome measure (presumably since using the time to progression hadn't shown that the $100,000 therapy offered an advantage). Consistent with its predecessors, this study also found survival was better with sipuleucel-T (25.8 months versus 21.7 months), although again, median time to progression was identical in both groups (14.6 weeks versus 14.4 weeks). Biologically, this result was puzzling: as an accompanying editorial commented, it is hard to understand how sipuleucel-T could prolong life without having any measurable effect on tumor growth.
Why do men with castration- refractory metastatic prostate cancer live longer with sipuleucel-T than with placebo? It's not clear. But one curious observation is that once the tumor progressed-which it did in 90% of people during the course of the study-physicians were free to treat patients with other anti-cancer regimens such as conventional chemotherapy, and more of the patients who had gotten sipuleucel-T opted for such treatment. It's possible that it was in fact the chemotherapy that contributed to the survival advantage in this group of otherwise healthy older men, although the mathematical models generated by the authors to adjust for differences in treatment after relapse dispute this interpretation.
It seems that the latest and greatest treatment for prostate cancer may not be so wonderful after all. And if it is approved by Medicare, it will almost certainly be used "off label," that is for other patients with castration-resistant prostate cancer, including those on narcotics for bone pain and with lung or liver metastases, patients who were excluded from the original studies. Physicians are legally allowed to use an approved treatment modality in any circumstance they think it might be effective. If Medicare approves immunotherapy without restrictions, the treatment is likely to be applied to thousands of men who are far older, sicker, and more impaired than the men in whom the treatment was tested. Whether these men will benefit at all is unknown-there are simply no studies that address that question. But if sipuleucel-T is of uncertain benefit in the healthiest men, it is even less likely to help those who have multiple other medical problems. Treating 1000 men with immunotherapy will cost Medicare $100 million. But what if it's 10,000 men? Do we really want to spend a billion dollars on a treatment that, at best, might extend life a few months and, at worst, will have no benefit at all but may cause fevers, chills, and tremors?
Politicians have finally recognized that we need to curb the rate of rise of expenditures in the Medicare program. The only sensible way to achieve this end is to require Medicare to function within a budget. And if we don't want to do this by simply limiting the amount of money that Medicare pays out to private insurance companies in the form of vouchers-an approach that will have no effect on the rate of rise of medical expenditures and will merely shift the cost from the federal government to the consumer-we will need to finally insist that Medicare make coverage decisions responsibly, taking cost into account. Medicare is constrained by law to cover treatments that are "reasonable and necessary." Surely it is not reasonable to approve a treatment that costs $100,000 unless it has clearly been shown to work. If the therapy is effective in some patients, its use should be restricted to the types of patients in whom it has proved useful. Finally, Medicare should be able to set the price it is willing to pay for such treatment based on its cost-effectiveness compared to alternative treatments. That's not government intrusion into the practice of medicine; it's common sense.
April 22, 2011
March 25, 2011
Priming the Pump
More bad news about dementia in America was released recently by the Alzheimer’s Association in its report, “Alzheimer’s Facts and Figures 2011.” Actually, this year’s report isn’t much different from last year’s except that the number of people with some form of dementia in the U.S. has gone from 5.3 million to 5.4 million. We’re on track to have between 11 and 16 million citizens with dementia by 2050, assuming there is no breakthrough in our ability to treat or prevent Alzheimer’s. And while many drugs are undergoing evaluation as treatment for this devastating brain disease, none has shown dramatic effectiveness. As the report states categorically, “No treatment is available to slow or stop the deterioration of brain cells in Alzheimer’s Disease.”
Americans spend an enormous amount of money on medical care for people with dementia: the total health care tab for 2011 is projected to reach $183 billion. We spend more on patients who have both heart disease and Alzheimer’s than on patients who have heart disease alone; the same is true for diabetes and a slew of other conditions. In part, this is because people with dementia tend to be older than their counterparts without the disease and are therefore likely to be sicker: according to some estimates, 43% of people 85 or older have dementia. But it also means that a great many people with Alzheimer’s disease undergo invasive, high tech medical treatment that they find frightening and painful. Not only can’t they understand the purpose of the treatment, but they might also not want intervention if they realized one of its main effects was to allow them to live long enough to develop more advanced dementia.
The one new part of this year’s report is the section on “early detection and diagnosis: benefit and challenges.” Early diagnosis has been championed by many authorities in the field, including the International Work Group for New Research Criteria for the Diagnosis of Alzheimer’s Disease. This group now recommends changing the diagnostic criteria for Alzheimer’s to include “biomarkers” (abnormal proteins found in the cerebrospinal fluid) or “imaging tests” (such as Positron Emission Tomography or PET scans). The section on early diagnosis in “Alzheimer’s Facts and Figures” enumerates a host of potential benefits—for example, the opportunity to plan for the future—but ignores the risks—such as generating anxiety in patients and families alike. The real reason for early diagnosis, as with other medical conditions, is to provide treatment which, when given early on, is more effective than if it is administered later. Unfortunately, the only treatment currently available is of hardly any benefit at all. As the report acknowledges, the 5 drugs approved by the FDA for use in Alzheimer’s “temporarily slow the worsening of symptoms for 6-12 months.” That’s the best we have—and only a minority of patients even experience this degree of benefit.
It is the chart listing “recent advances in use of biomarkers and brain images for diagnosis of dementia in living people” that reveals the real purpose of the growing emphasis on early diagnosis. To make the diagnosis early, we will need to use new tests for Alzheimer's. New tests mean greater profits for the manufacturers of those tests. Drug companies and device manufacturers are hungry for new markets and one of the biggest markets is older people at risk for Alzheimer’s disease. From the manufacturers’ perspective, screening and diagnosis are even better areas for investment than treatment because the number of people in whom such testing might be done is orders of magnitude larger. Everyone over 65 could be a candidate for a screening test—currently 39 million people in the U.S. And of course, if the test is negative, it will need to be repeated a few years later. We’ve already seen efforts to expand the use of expensive diagnostic tests for Alzheimer’s disease: the manufacturers of the PET scan, a sophisticated imaging device, have long been in search of new uses for their technology. While it is now widely used to follow the progression of disease in cancer patients, it was also advocated to diagnose Alzheimer’s disease. When the manufacturer sought approval from the Centers for Medicaid and Medicare Services for reimbursement of the scan in 2003, CMS turned down the request. There was simply no compelling evidence that PET scans are useful to diagnose Alzheimer’s. The companies who made PET scans were not pleased. One of the co-founders of the largest manufacturer (and a board member and major shareholder), happened to be friends with Ted Stevens, the Senator who was then head of the appropriations committee that controlled the purse strings of CMS. The upshot was that although there wasn’t a shred of new evidence suggesting that PET scans are important in the diagnosis of Alzheimer’s, the test was approved for Medicare coverage (ostensibly only if the goal is to distinguish Alzheimer’s disease from another far less common cause of dementia, fronto-temporal dementia).
Pharmaceutical companies like the idea of early diagnosis, too, because they want to be able to swoop in and offer a drug, however limited its benefit, to anyone who tests positive. The world’s largest drug company, Pfizer, lists six “Invest to Win” areas in its 2009 Annual Report. Number one on the list is Alzheimer’s disease. Now there’s nothing wrong with wanting to find a treatment for Alzheimer’s disease; on the contrary, it would be wonderful. And maybe one of the drugs that Pfizer is testing will turn out, against all the current evidence, to be truly beneficial. But at this point in time, the main purpose of early diagnosis is to have a ready market for whatever drugs emerge from the Pfizer pipeline, however minimal their effectiveness.
One day, when we have a drug that can stop the accumulation of the plaques and tangles that characterize Alzheimer’s disease in their tracks, early diagnosis will be important. In the meantime, relax and enjoy yourself. Do not rush out to have a lumbar puncture for the purpose of measuring “markers” for Alzheimer’s in the cerebrospinal fluid; do not succumb to pressure to have a PET scan. Occasionally, ignorance really is bliss.
Americans spend an enormous amount of money on medical care for people with dementia: the total health care tab for 2011 is projected to reach $183 billion. We spend more on patients who have both heart disease and Alzheimer’s than on patients who have heart disease alone; the same is true for diabetes and a slew of other conditions. In part, this is because people with dementia tend to be older than their counterparts without the disease and are therefore likely to be sicker: according to some estimates, 43% of people 85 or older have dementia. But it also means that a great many people with Alzheimer’s disease undergo invasive, high tech medical treatment that they find frightening and painful. Not only can’t they understand the purpose of the treatment, but they might also not want intervention if they realized one of its main effects was to allow them to live long enough to develop more advanced dementia.
The one new part of this year’s report is the section on “early detection and diagnosis: benefit and challenges.” Early diagnosis has been championed by many authorities in the field, including the International Work Group for New Research Criteria for the Diagnosis of Alzheimer’s Disease. This group now recommends changing the diagnostic criteria for Alzheimer’s to include “biomarkers” (abnormal proteins found in the cerebrospinal fluid) or “imaging tests” (such as Positron Emission Tomography or PET scans). The section on early diagnosis in “Alzheimer’s Facts and Figures” enumerates a host of potential benefits—for example, the opportunity to plan for the future—but ignores the risks—such as generating anxiety in patients and families alike. The real reason for early diagnosis, as with other medical conditions, is to provide treatment which, when given early on, is more effective than if it is administered later. Unfortunately, the only treatment currently available is of hardly any benefit at all. As the report acknowledges, the 5 drugs approved by the FDA for use in Alzheimer’s “temporarily slow the worsening of symptoms for 6-12 months.” That’s the best we have—and only a minority of patients even experience this degree of benefit.
It is the chart listing “recent advances in use of biomarkers and brain images for diagnosis of dementia in living people” that reveals the real purpose of the growing emphasis on early diagnosis. To make the diagnosis early, we will need to use new tests for Alzheimer's. New tests mean greater profits for the manufacturers of those tests. Drug companies and device manufacturers are hungry for new markets and one of the biggest markets is older people at risk for Alzheimer’s disease. From the manufacturers’ perspective, screening and diagnosis are even better areas for investment than treatment because the number of people in whom such testing might be done is orders of magnitude larger. Everyone over 65 could be a candidate for a screening test—currently 39 million people in the U.S. And of course, if the test is negative, it will need to be repeated a few years later. We’ve already seen efforts to expand the use of expensive diagnostic tests for Alzheimer’s disease: the manufacturers of the PET scan, a sophisticated imaging device, have long been in search of new uses for their technology. While it is now widely used to follow the progression of disease in cancer patients, it was also advocated to diagnose Alzheimer’s disease. When the manufacturer sought approval from the Centers for Medicaid and Medicare Services for reimbursement of the scan in 2003, CMS turned down the request. There was simply no compelling evidence that PET scans are useful to diagnose Alzheimer’s. The companies who made PET scans were not pleased. One of the co-founders of the largest manufacturer (and a board member and major shareholder), happened to be friends with Ted Stevens, the Senator who was then head of the appropriations committee that controlled the purse strings of CMS. The upshot was that although there wasn’t a shred of new evidence suggesting that PET scans are important in the diagnosis of Alzheimer’s, the test was approved for Medicare coverage (ostensibly only if the goal is to distinguish Alzheimer’s disease from another far less common cause of dementia, fronto-temporal dementia).
Pharmaceutical companies like the idea of early diagnosis, too, because they want to be able to swoop in and offer a drug, however limited its benefit, to anyone who tests positive. The world’s largest drug company, Pfizer, lists six “Invest to Win” areas in its 2009 Annual Report. Number one on the list is Alzheimer’s disease. Now there’s nothing wrong with wanting to find a treatment for Alzheimer’s disease; on the contrary, it would be wonderful. And maybe one of the drugs that Pfizer is testing will turn out, against all the current evidence, to be truly beneficial. But at this point in time, the main purpose of early diagnosis is to have a ready market for whatever drugs emerge from the Pfizer pipeline, however minimal their effectiveness.
One day, when we have a drug that can stop the accumulation of the plaques and tangles that characterize Alzheimer’s disease in their tracks, early diagnosis will be important. In the meantime, relax and enjoy yourself. Do not rush out to have a lumbar puncture for the purpose of measuring “markers” for Alzheimer’s in the cerebrospinal fluid; do not succumb to pressure to have a PET scan. Occasionally, ignorance really is bliss.
February 28, 2011
Aging in Black and White
“Never Say Die: The Myth and Marketing of the New Old Age,” a new book by Susan Jacoby, is a tour de force. If you can get beyond the strident rhetoric and the relentless anger, you will find a much needed dose of reality about aging. Jacoby’s perspective, much like the one I articulated in “The Denial of Aging: Perpetual Youth, Eternal Life, and Other Dangerous Fantasies,” is that frailty and dementia are part of aging for many, many people and death comes for us all. To pretend otherwise—and the hype about exercise and diet leads many to believe we can remain vigorous until we die peacefully in our sleep (if we die at all)—has pernicious consequences. Those consequences, as Jacoby argues, are that we die badly; we undergo needless pain and suffering, at great financial cost, in exchange for living longer in a condition of dependence and debility; and we neglect to provide the kinds of social and economic remedies that could support a dignified old age.
For all of Jacoby’s incisive analysis and prodigious research, she leaves out of her discussion the most difficult decisions that frail people must make about health care. She focuses on dying, certainly a critically important domain, but omits the choice faced by 80 or 85 year olds about whether or not to receive an implanted defibrillators or palliative chemotherapy or bypass surgery. It is all very well to talk about the absurdity of extending the life of a person after a massive stroke by tethering her to a ventilator in an intensive care unit. This is an approach that the overwhelming majority of older people do not want for themselves. When a medical intervention is invasive, expensive, and ultimately unsuccessful (the 85 year old with a massive stroke is near the end of life, no matter what treatment is administered), virtually all reasonable people would agree—if only the alternative were presented in these terms—that it should not be used. The challenge is to figure out what to do for the person with mild dementia who has had a stroke that selectively interferes with swallowing. Should she be given a feeding tube to provide nutrition artificially? Or should she be kept comfortable using ice chips and mouth swabs?
Jacoby finds Ted Kennedy’s approach to his malignant brain tumor an inspiring model: accept maximally aggressive care as long as there is a chance of regaining a satisfactory quality of life; when there is no longer any reasonable likelihood of improvement, then enroll in hospice. But what about treatments that have a 20% chance of improving quality of life—but an 80% chance of causing increased pain and suffering in the short run and failing to improve quality of life over the longer run? What if the chance of improvement is only 10%? Lest this sound like Abraham arguing with God about his plan to destroy Sodom and Gomorrah if there are still 50 wise men in the city (or 40 or 30), what if the chance is 50% but the 50% who don’t get better are instead excruciatingly miserable? What if the chance of temporary improvement is 50%, but the cost of the treatment will wipe out the patient’s savings and there is an alternative approach that will extend life by 2 months instead of 4 (a huge differential in oncology circles) but at far more modest cost?
Perhaps it’s not fair to criticize “Never Say Die” for what it could have dealt with but didn’t. After all, Jacoby has tackled a number of interesting issues: she talks about how the tribulations of old age disproportionately afflict women (true, in part since women live longer); she is at great pains to trace the historical origins of a youth-oriented culture at least to the Civil War (compelling for those of us who love history, but what would perhaps be more illuminating is a contemporary cross-cultural comparison of attitudes to old age); she skewers those who claim that ‘wisdom’ comes with old age, suggesting that there is continuity between our middle aged and older selves (yes, there are wise 45-year-olds and foolish 80-year-olds); and she gets a bit tangled up in the controversy about the ethics of longevity research, asserting forcefully that there’s nothing wrong with living longer but the problem is that longer life inevitably brings with it debilitating diseases (perhaps not fully appreciating the longevity researchers’ argument that finding the master switch for the aging process and learning to turn it off would enable us to live longer precisely because we wouldn’t develop one disease after another).
But in the end, Jacoby falls victim to what Thomas Cole, in his book “The Journey of Life: A Cultural History of Aging in America,”
calls the duality of old age: the historical tendency to swing from one pole (aging is glorious) to its opposite (aging is a time of unremitting misery). What we must aspire to instead is a more balanced, dialectical view that sees aging as multifaceted. Painting old age in shades of gray rather than in stark black and white would better serve the goal of helping us design medical care, long term care facilities, and socio-economic policies for the oldest old.
For all of Jacoby’s incisive analysis and prodigious research, she leaves out of her discussion the most difficult decisions that frail people must make about health care. She focuses on dying, certainly a critically important domain, but omits the choice faced by 80 or 85 year olds about whether or not to receive an implanted defibrillators or palliative chemotherapy or bypass surgery. It is all very well to talk about the absurdity of extending the life of a person after a massive stroke by tethering her to a ventilator in an intensive care unit. This is an approach that the overwhelming majority of older people do not want for themselves. When a medical intervention is invasive, expensive, and ultimately unsuccessful (the 85 year old with a massive stroke is near the end of life, no matter what treatment is administered), virtually all reasonable people would agree—if only the alternative were presented in these terms—that it should not be used. The challenge is to figure out what to do for the person with mild dementia who has had a stroke that selectively interferes with swallowing. Should she be given a feeding tube to provide nutrition artificially? Or should she be kept comfortable using ice chips and mouth swabs?
Jacoby finds Ted Kennedy’s approach to his malignant brain tumor an inspiring model: accept maximally aggressive care as long as there is a chance of regaining a satisfactory quality of life; when there is no longer any reasonable likelihood of improvement, then enroll in hospice. But what about treatments that have a 20% chance of improving quality of life—but an 80% chance of causing increased pain and suffering in the short run and failing to improve quality of life over the longer run? What if the chance of improvement is only 10%? Lest this sound like Abraham arguing with God about his plan to destroy Sodom and Gomorrah if there are still 50 wise men in the city (or 40 or 30), what if the chance is 50% but the 50% who don’t get better are instead excruciatingly miserable? What if the chance of temporary improvement is 50%, but the cost of the treatment will wipe out the patient’s savings and there is an alternative approach that will extend life by 2 months instead of 4 (a huge differential in oncology circles) but at far more modest cost?
Perhaps it’s not fair to criticize “Never Say Die” for what it could have dealt with but didn’t. After all, Jacoby has tackled a number of interesting issues: she talks about how the tribulations of old age disproportionately afflict women (true, in part since women live longer); she is at great pains to trace the historical origins of a youth-oriented culture at least to the Civil War (compelling for those of us who love history, but what would perhaps be more illuminating is a contemporary cross-cultural comparison of attitudes to old age); she skewers those who claim that ‘wisdom’ comes with old age, suggesting that there is continuity between our middle aged and older selves (yes, there are wise 45-year-olds and foolish 80-year-olds); and she gets a bit tangled up in the controversy about the ethics of longevity research, asserting forcefully that there’s nothing wrong with living longer but the problem is that longer life inevitably brings with it debilitating diseases (perhaps not fully appreciating the longevity researchers’ argument that finding the master switch for the aging process and learning to turn it off would enable us to live longer precisely because we wouldn’t develop one disease after another).
But in the end, Jacoby falls victim to what Thomas Cole, in his book “The Journey of Life: A Cultural History of Aging in America,”
calls the duality of old age: the historical tendency to swing from one pole (aging is glorious) to its opposite (aging is a time of unremitting misery). What we must aspire to instead is a more balanced, dialectical view that sees aging as multifaceted. Painting old age in shades of gray rather than in stark black and white would better serve the goal of helping us design medical care, long term care facilities, and socio-economic policies for the oldest old.
January 02, 2011
New Wine from NAPA?
In a rare moment of bipartisanship, Congress unanimously approved the National Alzheimer’s Project Act. The media called it “historic legislation” and said its passage was a “momentous victory.” But will NAPA, as it is being called, accomplish anything?
NAPA is not a plan of action: it calls for a task force to create a plan of action. Having recently participated in a corporate “value stream” that is intended to lead to the transformation of the way medical care is provided in the multi-specialty group practice where I work, I am aware of the prevailing faith in “planning to plan.” And maybe, just maybe, the interagency council that has been charged by NAPA to create a coordinated “National Alzheimer’s Disease Plan” will come up with a brilliant plan. And maybe Congress will fund the implementation of such a plan: 2 bills are already in the works which would provide for several key ingredients of any plan, research into the prevention and treatment of Alzheimer’s (the Alzheimer’s Breakthrough Act) and enhanced clinical services (the Health Outcomes, Planning and Education for Alzheimer’s Act).
Right now, the best we can do is to give the yet-to-be created council advice. So here are some sober reminders, historical precedents, useful metaphors, and desperate needs to consider:
Sober Reminders
There are currently no effective means of preventing Alzheimer’s disease. An NIH state-of-the-science conference held in April, 2010 concluded, after reviewing every study of a strategy intended to affect the onset of the disease, that “there is currently no evidence of even moderate scientific quality supporting the association of any modifiable risk factor…with reduced risk of Alzheimer’s disease.” The panel looked at dietary supplements, prescription drugs, non-prescription drugs, diet, exercise, and social engagement and could recommend nothing.
Brain diseases are notoriously hard to treat. We don’t have a cure for any non-infectious brain disease. For most of the degenerative neurologic diseases such as multiple sclerosis, there is little in the way of effective treatment. The central nervous system disease for which we arguably have the best treatment, Parkinson’s disease, remains a progressive, debilitating disorder.
The blood brain barrier makes treatment particularly challenging. The brain is uniquely well-defended against penetration by drugs and other chemicals. The so-called “blood-brain barrier” protects individuals from toxins—and from potentially effective treatment.
Historical Precedents
The Manhattan Project. Everyone loves to cite the Manhattan Project as an example of a government-run project that solved an important and difficult problem. But the creation of nuclear weapons was accomplished by rounding up the smartest physicists and mathematicians in the country and secluding them in Los Alamos until they produced a bomb. It was carried out during wartime. While there were some thorny theoretical problems to be solved, much of the process was essentially an engineering challenge, it involved applying known science to a specific problem. Extrapolating to Alzheimer’s disease research is perilous at best.
Attack on AIDS.
Money was poured into AIDS research, with some stunning results, at least in the US. But unlike Alzheimer’s disease, AIDS is an infectious illness. It is also worth noting that the outcome of the research was containment, not cure, which may likewise prove to be a more realistic goal of Alzheimer’s research than eradication of the disease.
The War on Cancer.
President Nixon declared war on cancer in 1971. We’re still fighting that war, which makes it America’s longest war, longer even than the wars in Afghanistan and Iraq. Between 1971 and 2008, according to an article in Newsweek, the US government, private companies, and foundations, spent $200 billion on the quest for a cure. Progress has been made on a number of fronts, as Siddhartha Mukherjee’s magisterial book, “The Emperor of All Maladies,”
documents. The age-adjusted death rate from cancer rose from 199/100,000 in 1975 to peak at 215/100,000 in 1991, but has since fallen, reaching a low of 184/100,000 in 2005. The death rate from breast cancer fell from 31/100,000 to 24/100,000 in the same period and mortality from colorectal cancer went from 28/100,000 to 17/100,000. But lung cancer mortality has not improved and lung cancer is the most common form of cancer. Cancer stands poised to surpass cardiovascular disease as the leading cause of death in the US. Declaring war does not guarantee victory.
Useful Metaphors
Addressing terrorism is unlike fighting a conventional war. Since the end of the Second World War, the US has been struggling to shape military policy to new realities. Nuclear weapons changed the playing field. So did insurgencies and terrorism. Strategies that made sense in WW II did not work in Vietnam and are not working in Afghanistan. It is dangerous to use old metaphors in dealing with new problems, whether in international conflict or disease.
Desperate Needs
Planning for the future must not neglect the needs of today. There are people alive today with Alzheimer’s disease—an estimated 5.3 million in the US. There will be people with this disease for years to come: by 2050, the number of Americans with the disorder could reach 16 million. It’s important to conduct basic research in the hope of postponing the age of onset of Alzheimer’s disease, containing the disorder, or possibly even curing it. But we must not neglect the realities of today. We have to devote resources to designing better institutional arrangements for individuals with Alzheimer’s. We have to do a better job providing palliative care for sufferers from dementia. The good news is that this is one area of medicine where doing the right thing will save money.
NAPA is not a plan of action: it calls for a task force to create a plan of action. Having recently participated in a corporate “value stream” that is intended to lead to the transformation of the way medical care is provided in the multi-specialty group practice where I work, I am aware of the prevailing faith in “planning to plan.” And maybe, just maybe, the interagency council that has been charged by NAPA to create a coordinated “National Alzheimer’s Disease Plan” will come up with a brilliant plan. And maybe Congress will fund the implementation of such a plan: 2 bills are already in the works which would provide for several key ingredients of any plan, research into the prevention and treatment of Alzheimer’s (the Alzheimer’s Breakthrough Act) and enhanced clinical services (the Health Outcomes, Planning and Education for Alzheimer’s Act).
Right now, the best we can do is to give the yet-to-be created council advice. So here are some sober reminders, historical precedents, useful metaphors, and desperate needs to consider:
Sober Reminders
There are currently no effective means of preventing Alzheimer’s disease. An NIH state-of-the-science conference held in April, 2010 concluded, after reviewing every study of a strategy intended to affect the onset of the disease, that “there is currently no evidence of even moderate scientific quality supporting the association of any modifiable risk factor…with reduced risk of Alzheimer’s disease.” The panel looked at dietary supplements, prescription drugs, non-prescription drugs, diet, exercise, and social engagement and could recommend nothing.
Brain diseases are notoriously hard to treat. We don’t have a cure for any non-infectious brain disease. For most of the degenerative neurologic diseases such as multiple sclerosis, there is little in the way of effective treatment. The central nervous system disease for which we arguably have the best treatment, Parkinson’s disease, remains a progressive, debilitating disorder.
The blood brain barrier makes treatment particularly challenging. The brain is uniquely well-defended against penetration by drugs and other chemicals. The so-called “blood-brain barrier” protects individuals from toxins—and from potentially effective treatment.
Historical Precedents
The Manhattan Project. Everyone loves to cite the Manhattan Project as an example of a government-run project that solved an important and difficult problem. But the creation of nuclear weapons was accomplished by rounding up the smartest physicists and mathematicians in the country and secluding them in Los Alamos until they produced a bomb. It was carried out during wartime. While there were some thorny theoretical problems to be solved, much of the process was essentially an engineering challenge, it involved applying known science to a specific problem. Extrapolating to Alzheimer’s disease research is perilous at best.
Attack on AIDS.
Money was poured into AIDS research, with some stunning results, at least in the US. But unlike Alzheimer’s disease, AIDS is an infectious illness. It is also worth noting that the outcome of the research was containment, not cure, which may likewise prove to be a more realistic goal of Alzheimer’s research than eradication of the disease.
The War on Cancer.
President Nixon declared war on cancer in 1971. We’re still fighting that war, which makes it America’s longest war, longer even than the wars in Afghanistan and Iraq. Between 1971 and 2008, according to an article in Newsweek, the US government, private companies, and foundations, spent $200 billion on the quest for a cure. Progress has been made on a number of fronts, as Siddhartha Mukherjee’s magisterial book, “The Emperor of All Maladies,”
documents. The age-adjusted death rate from cancer rose from 199/100,000 in 1975 to peak at 215/100,000 in 1991, but has since fallen, reaching a low of 184/100,000 in 2005. The death rate from breast cancer fell from 31/100,000 to 24/100,000 in the same period and mortality from colorectal cancer went from 28/100,000 to 17/100,000. But lung cancer mortality has not improved and lung cancer is the most common form of cancer. Cancer stands poised to surpass cardiovascular disease as the leading cause of death in the US. Declaring war does not guarantee victory.
Useful Metaphors
Addressing terrorism is unlike fighting a conventional war. Since the end of the Second World War, the US has been struggling to shape military policy to new realities. Nuclear weapons changed the playing field. So did insurgencies and terrorism. Strategies that made sense in WW II did not work in Vietnam and are not working in Afghanistan. It is dangerous to use old metaphors in dealing with new problems, whether in international conflict or disease.
Desperate Needs
Planning for the future must not neglect the needs of today. There are people alive today with Alzheimer’s disease—an estimated 5.3 million in the US. There will be people with this disease for years to come: by 2050, the number of Americans with the disorder could reach 16 million. It’s important to conduct basic research in the hope of postponing the age of onset of Alzheimer’s disease, containing the disorder, or possibly even curing it. But we must not neglect the realities of today. We have to devote resources to designing better institutional arrangements for individuals with Alzheimer’s. We have to do a better job providing palliative care for sufferers from dementia. The good news is that this is one area of medicine where doing the right thing will save money.
December 06, 2010
News of a Life in Review
The father of modern geriatric medicine, Robert Butler, died last summer at the age of 83. His contributions to the study of aging and to the care of older people were prodigious: he was the founding director of the National Institute on Aging, the division of the National Institutes of Health devoted exclusively to the elderly; he persuaded Mount Sinai School of Medicine to establish the first ever Department of Geriatrics-and was promptly appointed its first chairman; his book, Why Survive: Being Old in America, published in 1975, made the case that America was "ageist" and argued forcefully that views of older people as feeble and "senile" reflected prejudice and ignorance, analogous to "racism."
Less well-known is Butler's endorsement of the idea of a "life review." Older individuals frequently look back on their lives, trying to create a coherent narrative that helps give meaning to their lives. Butler coined the term "life review" for this process and, far from mocking it as a sign of incipient dementia, as was the fashion in the 1950s, he encouraged the practice, suggesting it gave older people the opportunity to find what Erik Erikson called "ego integrity" in the final stage of life.
American medicine, by contrast, has focused on finding a quick fix to the problems of aging. Vitamin E, an anti-oxidant, was heralded as a miracle drug, until it turned out that instead of preventing heart disease and cancer, it had no effect in preventing either one and seemed to increase the risk of heart failure. Estrogen for women met a similar fate: touted as the fountain of youth and alleged to prevent such age-associated ailments as dementia and coronary artery disease, it was found to be useless in protecting against dementia and to increase the rate of heart disease. Vitamin D, the most recent candidate for anti-aging potion, just this month met the same fate. The Institute of Medicine concluded that vitamin D had not been shown to boost immunity, to prevent cancer, or to stave off diabetes.
The search for a magic bullet to prevent aging has led us to neglect the quality of life for those who are already old, and who may be frail or demented.
One strategy we already have for improving life satisfaction in old age is life review. A series of small studies this past year have confirmed the utility of life review for psychological well-being. One study of reminiscence therapy in Taiwan nursing homes found less loneliness, less depression, and greater psychological well-being in the experimental group. Similar results emerged from a randomized study conducted in ten Danish nursing homes. A Dutch randomized trial conducted in the community found that enrollment in a life review course called "Looking for Meaning" reduced depressive symptoms, a result that persisted at six months.
Unlike medications, life review has virtually no side effects. But unlike new drugs covered by patents, it will not enrich anybody and has no powerful corporate sponsors (Venlafaxine, an antidepressant, cost $70 for a one-month supply, according to Drugstore.com, and Quetiapine, an antipsychotic commonly used for symptoms such as agitation, costs $90 for a one-month supply).
I recently engaged in a limited form of life review with my parents, who are now 85 and 86. I interviewed them at length about their experiences during their first 25 years. Both were born Jewish in Germany, my mother in the port city of Stettin (now Szczecin, Poland) and my father in the small East Prussian town of Osterode (now Ostroda, also in Poland). In January, 1939, they both left Germany forever on a children's transport to Belgium. When Germany invaded Belgium in May, 1940, they escaped by train to the south of France as part of a group of 100 refugee children. There they remained, in a children's colony supported by the Swiss Red Cross, until they were threatened with deportation to Nazi death camps and fled, in 2 separate expeditions, over the border to Switzerland. My interviews focused on their early lives in Germany and their experiences as refugees, first in Belgium, then in France, and next in Switzerland. After the war, refused residency by the Swiss, they immigrated: my father to Brazil and from there to the U.S., and my mother directly to the U.S.
The process of telling their story, while sometimes painful, was clearly valuable to my parents. They found it helped them make sense of their lives to think about how their early experiences affected them as American citizens and as parents. They felt there were lessons to be learned-lessons about countries' responsibilities to refugees and about what it means to act humanely-which they were eager to communicate and hence were gratified to see their story made public in my recently released book, Once They Had a Country: Two Teenage Refugees in the Second World War.
So as we salute Robert Butler for his many invaluable contributions to geriatrics, let us not forget the humble life review.
Less well-known is Butler's endorsement of the idea of a "life review." Older individuals frequently look back on their lives, trying to create a coherent narrative that helps give meaning to their lives. Butler coined the term "life review" for this process and, far from mocking it as a sign of incipient dementia, as was the fashion in the 1950s, he encouraged the practice, suggesting it gave older people the opportunity to find what Erik Erikson called "ego integrity" in the final stage of life.
American medicine, by contrast, has focused on finding a quick fix to the problems of aging. Vitamin E, an anti-oxidant, was heralded as a miracle drug, until it turned out that instead of preventing heart disease and cancer, it had no effect in preventing either one and seemed to increase the risk of heart failure. Estrogen for women met a similar fate: touted as the fountain of youth and alleged to prevent such age-associated ailments as dementia and coronary artery disease, it was found to be useless in protecting against dementia and to increase the rate of heart disease. Vitamin D, the most recent candidate for anti-aging potion, just this month met the same fate. The Institute of Medicine concluded that vitamin D had not been shown to boost immunity, to prevent cancer, or to stave off diabetes.
The search for a magic bullet to prevent aging has led us to neglect the quality of life for those who are already old, and who may be frail or demented.
One strategy we already have for improving life satisfaction in old age is life review. A series of small studies this past year have confirmed the utility of life review for psychological well-being. One study of reminiscence therapy in Taiwan nursing homes found less loneliness, less depression, and greater psychological well-being in the experimental group. Similar results emerged from a randomized study conducted in ten Danish nursing homes. A Dutch randomized trial conducted in the community found that enrollment in a life review course called "Looking for Meaning" reduced depressive symptoms, a result that persisted at six months.
Unlike medications, life review has virtually no side effects. But unlike new drugs covered by patents, it will not enrich anybody and has no powerful corporate sponsors (Venlafaxine, an antidepressant, cost $70 for a one-month supply, according to Drugstore.com, and Quetiapine, an antipsychotic commonly used for symptoms such as agitation, costs $90 for a one-month supply).
I recently engaged in a limited form of life review with my parents, who are now 85 and 86. I interviewed them at length about their experiences during their first 25 years. Both were born Jewish in Germany, my mother in the port city of Stettin (now Szczecin, Poland) and my father in the small East Prussian town of Osterode (now Ostroda, also in Poland). In January, 1939, they both left Germany forever on a children's transport to Belgium. When Germany invaded Belgium in May, 1940, they escaped by train to the south of France as part of a group of 100 refugee children. There they remained, in a children's colony supported by the Swiss Red Cross, until they were threatened with deportation to Nazi death camps and fled, in 2 separate expeditions, over the border to Switzerland. My interviews focused on their early lives in Germany and their experiences as refugees, first in Belgium, then in France, and next in Switzerland. After the war, refused residency by the Swiss, they immigrated: my father to Brazil and from there to the U.S., and my mother directly to the U.S.
The process of telling their story, while sometimes painful, was clearly valuable to my parents. They found it helped them make sense of their lives to think about how their early experiences affected them as American citizens and as parents. They felt there were lessons to be learned-lessons about countries' responsibilities to refugees and about what it means to act humanely-which they were eager to communicate and hence were gratified to see their story made public in my recently released book, Once They Had a Country: Two Teenage Refugees in the Second World War.
So as we salute Robert Butler for his many invaluable contributions to geriatrics, let us not forget the humble life review.
August 16, 2010
The Alzheimer's Revolution?
First a seemingly arcane debate at a medical conference about the criteria for diagnosing Alzheimer’s disease made news; then an article in a neurology journal was widely touted as showing that a spinal fluid test was “100% accurate in predicting Alzheimer’s.”
Are we on the cusp of a revolution? Is there truly a new way to think about this formidable disease—and is a cure finally at hand?
What we know now is that sometime in their mid- or late-fifties, individuals who are destined to develop Alzheimer’s disease begin accumulating a protein called amyloid-beta in their brains. This material clumps together to form plaques, the very same plaques seen by Alois Alzheimer under the microscope back in 1905, when he established early criteria for the disease. In the past, such plaques could only be identified by brain biopsy. Today, their presence can be inferred from “biomarkers” such as a low level of amyloid-beta in the cerebrospinal fluid (CSF) or specific changes on a PET or MRI scan.
The proposed new diagnostic criteria for Alzheimer’s disease reflect these biochemical findings. They do not require that a person have a special scan or a lumbar puncture to make the diagnosis. In fact, they define “probable Alzheimer’s disease dementia” based on the insidious onset of symptoms, a clear-cut history of worsening cognition, and certain cognitive deficits present on history and examination. The role of biomarkers—low CSF amyloid beta, elevated CSF tau, or specified abnormalities on either PET or MRI scans)—is solely to “enhance” the diagnosis, that is to slightly increase its certainty.
More noteworthy than the suggested diagnostic criteria is the recommendation that a syndrome of “preclinical Alzheimer’s disease” be defined. This recognizes the reality that Alzheimer’s disease is years in developing and that the opportunity for intervening to prevent the disease will almost surely arise during this developmental phase. Preclinical AD is defined based solely on biomarker evidence of amyloid beta accumulation or of early neurodegeneration. It requires either measurement of CSF biomarkers or a specialized scan.
In the setting of these proposed definitions, the new study from the Archives of Neurology is very intriguing. It reports on a test of the CSF fluid that measures both amyloid and tau and combines the results in a way that helps predict whether the patient has AD, or is healthy but likely to develop AD later on. The researchers conducted the study as part of a larger “Alzheimer’s Disease Neuroimaging Initiative” in which they followed a large group of individuals over time, some who were clinically normal, some who had Mild Cognitive Impairment(MCI--a state that often progresses to full-blown dementia), and some who were clinically diagnosed as having Alzheimer’s disease. The subset of this population who agreed to have a lumbar puncture formed the study sample for the Archives work: a total of 114 clinically normal individuals, 200 with MCI, and 102 with clinical evidence of Alzheimer’s. Based on this group, the scientists were able to define a “biomarker mixture” that was abnormal in 90% of those with dementia, 72% of those with Mild Cognitive Impairment, and 36% of those who were cognitively normal. When they tested their model in 2 other groups—one group of 68 people with autopsy-confirmed Alzheimer’s and one group of 57 patients with MCI who were followed for 5 years—they found that the biomarker mixture correctly identified 94% of those in the first group and all of those in the second group who progressed to full-blown dementia.
What all this means is not that patients with a clinical diagnosis of Alzheimer’s disease or of MCI should have a lumbar puncture or a special scan. It decidedly does not mean that cognitively intact older individuals should have their biomarkers measured to see if they are likely to get Alzheimer’s. What it does mean is that we now have the opportunity to do research on healthy people and on those with MCI to see if there is a drug that can prevent the progressive deposition of amyloid that appears to cause full blown Alzheimer’s.
The only problem with this approach is that currently no such drugs have been definitively identified. There are a host of putative disease-modifying agents: vaccines that stimulate the body to develop antibodies against amyloid (which sort of work but with the side effect of causing encephalitis, a brain inflammation), drugs that bind amyloid (which so far have been found to decrease the level of biomarkers but not to affect cognition), and chemicals that interfere with the enzyme that cleaves the abnormal amyloid from a larger precursor protein (which also do what they’re supposed to do biochemically but have not improved cognition).
The hope is that the newly defined preclinical syndrome will encourage researchers to dare to intervene before individuals have any abnormal symptoms. Putting the focus of research squarely on influencing the prodromal period may allow us to prevent or at least delay the progression of Alzheimer’s.
Is this a revolution? It is certainly a conceptual revolution. It embodies our best hope for intervening in the cascade of biochemical events that produces the leading form of dementia. Will it succeed? That remains to be seen.
Are we on the cusp of a revolution? Is there truly a new way to think about this formidable disease—and is a cure finally at hand?
What we know now is that sometime in their mid- or late-fifties, individuals who are destined to develop Alzheimer’s disease begin accumulating a protein called amyloid-beta in their brains. This material clumps together to form plaques, the very same plaques seen by Alois Alzheimer under the microscope back in 1905, when he established early criteria for the disease. In the past, such plaques could only be identified by brain biopsy. Today, their presence can be inferred from “biomarkers” such as a low level of amyloid-beta in the cerebrospinal fluid (CSF) or specific changes on a PET or MRI scan.
The proposed new diagnostic criteria for Alzheimer’s disease reflect these biochemical findings. They do not require that a person have a special scan or a lumbar puncture to make the diagnosis. In fact, they define “probable Alzheimer’s disease dementia” based on the insidious onset of symptoms, a clear-cut history of worsening cognition, and certain cognitive deficits present on history and examination. The role of biomarkers—low CSF amyloid beta, elevated CSF tau, or specified abnormalities on either PET or MRI scans)—is solely to “enhance” the diagnosis, that is to slightly increase its certainty.
More noteworthy than the suggested diagnostic criteria is the recommendation that a syndrome of “preclinical Alzheimer’s disease” be defined. This recognizes the reality that Alzheimer’s disease is years in developing and that the opportunity for intervening to prevent the disease will almost surely arise during this developmental phase. Preclinical AD is defined based solely on biomarker evidence of amyloid beta accumulation or of early neurodegeneration. It requires either measurement of CSF biomarkers or a specialized scan.
In the setting of these proposed definitions, the new study from the Archives of Neurology is very intriguing. It reports on a test of the CSF fluid that measures both amyloid and tau and combines the results in a way that helps predict whether the patient has AD, or is healthy but likely to develop AD later on. The researchers conducted the study as part of a larger “Alzheimer’s Disease Neuroimaging Initiative” in which they followed a large group of individuals over time, some who were clinically normal, some who had Mild Cognitive Impairment(MCI--a state that often progresses to full-blown dementia), and some who were clinically diagnosed as having Alzheimer’s disease. The subset of this population who agreed to have a lumbar puncture formed the study sample for the Archives work: a total of 114 clinically normal individuals, 200 with MCI, and 102 with clinical evidence of Alzheimer’s. Based on this group, the scientists were able to define a “biomarker mixture” that was abnormal in 90% of those with dementia, 72% of those with Mild Cognitive Impairment, and 36% of those who were cognitively normal. When they tested their model in 2 other groups—one group of 68 people with autopsy-confirmed Alzheimer’s and one group of 57 patients with MCI who were followed for 5 years—they found that the biomarker mixture correctly identified 94% of those in the first group and all of those in the second group who progressed to full-blown dementia.
What all this means is not that patients with a clinical diagnosis of Alzheimer’s disease or of MCI should have a lumbar puncture or a special scan. It decidedly does not mean that cognitively intact older individuals should have their biomarkers measured to see if they are likely to get Alzheimer’s. What it does mean is that we now have the opportunity to do research on healthy people and on those with MCI to see if there is a drug that can prevent the progressive deposition of amyloid that appears to cause full blown Alzheimer’s.
The only problem with this approach is that currently no such drugs have been definitively identified. There are a host of putative disease-modifying agents: vaccines that stimulate the body to develop antibodies against amyloid (which sort of work but with the side effect of causing encephalitis, a brain inflammation), drugs that bind amyloid (which so far have been found to decrease the level of biomarkers but not to affect cognition), and chemicals that interfere with the enzyme that cleaves the abnormal amyloid from a larger precursor protein (which also do what they’re supposed to do biochemically but have not improved cognition).
The hope is that the newly defined preclinical syndrome will encourage researchers to dare to intervene before individuals have any abnormal symptoms. Putting the focus of research squarely on influencing the prodromal period may allow us to prevent or at least delay the progression of Alzheimer’s.
Is this a revolution? It is certainly a conceptual revolution. It embodies our best hope for intervening in the cascade of biochemical events that produces the leading form of dementia. Will it succeed? That remains to be seen.
July 01, 2010
One Hundred Years of Alzheimer's Disease
One hundred years ago, the eminent German physician, Emil Kraepelin, published the eighth edition of his very successful textbook on psychiatry. It wasn't terribly different from the preceding version, but one small change would prove to have enduring consequences. Several neurologists and psychiatrists had described a disorder that looked very much like the dementia associated with old age but which afflicted people as young as 50. Kraepelin gave the disease a name. He called it "Alzheimer's disease," based on a case report that the neuropathologist Alois Alzheimer had presented in 1906. The name stuck although "Alzheimer's disease," was ultimately found to be indistinguishable from age-related dementia. What have we learned about the disease in the ensuing 100 years? The Alzheimer's Society's new report, Alzheimer's Facts and Figures 2010 gives us a snapshot of the disease as we know it today.
For 100 years there has been debate about the cause of dementia. Is it caused by plaques and tangles, the abnormal material that Alois Alzheimer observed under the microscope when he examined the brain of his patient, Frau Auguste D, after her death? Or is it a vascular condition, due to hardening of the arteries? For the last several decades, physicians have been confident that there are several distinct forms of dementia, with Alzheimer's disease and vascular or multi-infarct dementia discrete entities. But now the lines are blurring: a new autopsy study suggests that many cases of dementia are due to a mixture of several problems. By examining the brains of older individuals who had clinical evidence of Alzheimer's disease during life, scientists found that less than half of them had Alzheimer's disease alone. Fully one-third had infarcts (strokes) as well as Alzheimer's changes in their brains. About 15% had changes of Parkinson's disease in addition to Alzheimer's. These findings are not merely of academic interest: if it takes several distinct processes occurring simultaneously to produce dementia, there are potential therapeutic implications. Perhaps it will sufficient to intervene in just one of the processes-or maybe it will be necessary to strike all the contributors to the disease at once.
When Alzheimer described his patient, Frau Auguste D, a woman who first presented at age 51 with memory loss, paranoia, and the inability to care for herself, dementia was relatively rare. Most cases of dementia, after all, arise in people over age 65 and life expectancy in Germany in the early 20th century was only 60 years. The latest prevalence data show that today 5.3 million Americans have Alzheimer's disease or some other form of dementia, 5.1 million of whom are 65 years of age or older. The disease disproportionately affects women-which is partly but not entirely due to the fact that women live longer than men. A total of 10% of men and 16% of women over age 70 have dementia.
What Kraepelin and Alzheimer did not fully appreciate but what we know now is that dementia is a terminal illness: it is the 5th leading cause of death in people over age 65. But most people with dementia also have other chronic diseases, which makes sorting out what actually causes death is tricky: fully 60% of Medicare patients with dementia have high blood pressure, 26% have coronary artery disease, 23% have diabetes, and 25% show the residual effects of strokes.
Caring for individuals with dementia was sometimes a challenge even in Alzheimer's day-Frau D. had to be institutionalized because her behavior was so difficult to manage. The situation today is orders of magnitude more problematic. The number of people with dementia is growing dramatically, but the numbers of trained geriatric professionals (physicians, nurses, social workers) is not. Right now there are a paltry 7128 physicians who are board certified in geriatrics, with the projected need by 2030 estimated at 36,000 and no evidence that more doctors are going into the field. Even more worrisome is the lack of personal caregivers. Currently most of the direct care for people with dementia is provided by family and friends: 11 million unpaid caregivers provide a stunning 12.5 billion hours of care annually, or about 22 hours/week. As the population with dementia increases, it is far from clear how we will provide adequate professional and non-professional care.
In 1910, medical technology was essentially nonexistent. In 2010, it is widespread, especially in older people and even more so in older people with dementia. Medicare beneficiaries with dementia are 3 times more likely than their non-demented counterparts to be hospitalized. Looked at differently, at any point in time about one-fourth of all hospitalized patients over age 65 have dementia. Reflecting this trend, Medicare spends $15,145/year for each person with dementia compared to $5272/year for each person without dementia-and these figures do not include long term nursing home care, which is not covered by Medicare. What these numbers mean is that people with dementia receive is the same high tech, life-prolonging treatment that non-demented patients receive-multiplied by three both because they tend to have other chronic diseases and because they cannot articulate what exactly is bothering them, resulting int their being subjected to even more tests than other people. At first glance this might seem like a good thing, indicating that patients with dementia are not discriminated against. But instituting aggressive, life-prolonging therapy in people who have a terminal disease is of questionable benefit, particularly when it both causes suffering (people with dementia do not understand why they are receiving painful or frightening procedures) and is hugely expensive.
Kraepelin and Alzheimer lived in an ethnically and racially homogeneous society. Contemporary America is ethnically diverse and racial disparities in medical care are widespread. What is particularly striking is new evidence that older African Americans have twice the risk of developing dementia as do their white counterparts. The Washington Heights-Inwood Columbia Aging Program found that among people 85 years of age or older, the prevalence of dementia is 30.2% in whites, 58.6% in blacks, and 62.9% in Hispanics. The high rate of hypertension, diabetes, stroke, and coronary disease in African Americans and Hispanics may be responsible for the disparities. There is some hope that prevention of these conditions will ultimately be found to prevent dementia, although a recent NIH state-of-the-science conference concluded that "there is currently no evidence considered to be of even moderate scientific quality supporting the association of any modifiable factor...with reduced risk of Alzheimer's disease."
The centennial of Kraepelin's momentous naming decision is passing almost unnoticed. It should stimulate renewed dedication to addressing the challenges of caring for the growing numbers of patients and families devastated by Alzheimer's disease.
For 100 years there has been debate about the cause of dementia. Is it caused by plaques and tangles, the abnormal material that Alois Alzheimer observed under the microscope when he examined the brain of his patient, Frau Auguste D, after her death? Or is it a vascular condition, due to hardening of the arteries? For the last several decades, physicians have been confident that there are several distinct forms of dementia, with Alzheimer's disease and vascular or multi-infarct dementia discrete entities. But now the lines are blurring: a new autopsy study suggests that many cases of dementia are due to a mixture of several problems. By examining the brains of older individuals who had clinical evidence of Alzheimer's disease during life, scientists found that less than half of them had Alzheimer's disease alone. Fully one-third had infarcts (strokes) as well as Alzheimer's changes in their brains. About 15% had changes of Parkinson's disease in addition to Alzheimer's. These findings are not merely of academic interest: if it takes several distinct processes occurring simultaneously to produce dementia, there are potential therapeutic implications. Perhaps it will sufficient to intervene in just one of the processes-or maybe it will be necessary to strike all the contributors to the disease at once.
When Alzheimer described his patient, Frau Auguste D, a woman who first presented at age 51 with memory loss, paranoia, and the inability to care for herself, dementia was relatively rare. Most cases of dementia, after all, arise in people over age 65 and life expectancy in Germany in the early 20th century was only 60 years. The latest prevalence data show that today 5.3 million Americans have Alzheimer's disease or some other form of dementia, 5.1 million of whom are 65 years of age or older. The disease disproportionately affects women-which is partly but not entirely due to the fact that women live longer than men. A total of 10% of men and 16% of women over age 70 have dementia.
What Kraepelin and Alzheimer did not fully appreciate but what we know now is that dementia is a terminal illness: it is the 5th leading cause of death in people over age 65. But most people with dementia also have other chronic diseases, which makes sorting out what actually causes death is tricky: fully 60% of Medicare patients with dementia have high blood pressure, 26% have coronary artery disease, 23% have diabetes, and 25% show the residual effects of strokes.
Caring for individuals with dementia was sometimes a challenge even in Alzheimer's day-Frau D. had to be institutionalized because her behavior was so difficult to manage. The situation today is orders of magnitude more problematic. The number of people with dementia is growing dramatically, but the numbers of trained geriatric professionals (physicians, nurses, social workers) is not. Right now there are a paltry 7128 physicians who are board certified in geriatrics, with the projected need by 2030 estimated at 36,000 and no evidence that more doctors are going into the field. Even more worrisome is the lack of personal caregivers. Currently most of the direct care for people with dementia is provided by family and friends: 11 million unpaid caregivers provide a stunning 12.5 billion hours of care annually, or about 22 hours/week. As the population with dementia increases, it is far from clear how we will provide adequate professional and non-professional care.
In 1910, medical technology was essentially nonexistent. In 2010, it is widespread, especially in older people and even more so in older people with dementia. Medicare beneficiaries with dementia are 3 times more likely than their non-demented counterparts to be hospitalized. Looked at differently, at any point in time about one-fourth of all hospitalized patients over age 65 have dementia. Reflecting this trend, Medicare spends $15,145/year for each person with dementia compared to $5272/year for each person without dementia-and these figures do not include long term nursing home care, which is not covered by Medicare. What these numbers mean is that people with dementia receive is the same high tech, life-prolonging treatment that non-demented patients receive-multiplied by three both because they tend to have other chronic diseases and because they cannot articulate what exactly is bothering them, resulting int their being subjected to even more tests than other people. At first glance this might seem like a good thing, indicating that patients with dementia are not discriminated against. But instituting aggressive, life-prolonging therapy in people who have a terminal disease is of questionable benefit, particularly when it both causes suffering (people with dementia do not understand why they are receiving painful or frightening procedures) and is hugely expensive.
Kraepelin and Alzheimer lived in an ethnically and racially homogeneous society. Contemporary America is ethnically diverse and racial disparities in medical care are widespread. What is particularly striking is new evidence that older African Americans have twice the risk of developing dementia as do their white counterparts. The Washington Heights-Inwood Columbia Aging Program found that among people 85 years of age or older, the prevalence of dementia is 30.2% in whites, 58.6% in blacks, and 62.9% in Hispanics. The high rate of hypertension, diabetes, stroke, and coronary disease in African Americans and Hispanics may be responsible for the disparities. There is some hope that prevention of these conditions will ultimately be found to prevent dementia, although a recent NIH state-of-the-science conference concluded that "there is currently no evidence considered to be of even moderate scientific quality supporting the association of any modifiable factor...with reduced risk of Alzheimer's disease."
The centennial of Kraepelin's momentous naming decision is passing almost unnoticed. It should stimulate renewed dedication to addressing the challenges of caring for the growing numbers of patients and families devastated by Alzheimer's disease.
May 26, 2010
Say It Isn't So
My very first post on "Perspectives on Aging" dealt with dementia. I reported on a study that found exercise could decrease the risk of becoming demented. Since then I've blogged about dementia in general and Alzheimer's disease in particular 5 more times without a whole lot of encouraging news. The bad news just got a little worse: a recent National Institutes of Health "state-of-the-science" conference concluded that although a few tantalizing studies have suggested that exercise or social engagement or crossword puzzles could fend off dementia, a systematic evaluation fails to confirm these findings.
Dementia is unfortunately a very common condition which more and more people are developing as the population ages. At last count, 5.4 million Americans had Alzheimer's disease. Medications to treat Alzheimer's are mediocre-the most positive statement the American Psychiatric Association could make in a recent practice guideline for the most effective drugs, the cholinesterase inhibitors, is that they have a "modest" effect in a "substantial minority" of patients. Hardly a ringing endorsement. The antipsychotics, drugs often prescribed to treat the behavioral manifestations of dementia, have been associated with a small increased risk of death-which might be an acceptable price to pay if they worked, but they rarely do. Despite the scientific progress in the understanding of how Alzheimer's disease develops-and we know infinitely more today than Alois Alzheimer did in 1906 when he peered through the microscope and found plaques and tangles outside and inside (respectively) the neurons of his former patient, Auguste D-the prognosis for effective intervention is poor.
The new NIH report is very blunt: "There is currently no evidence considered to be of even moderate scientific quality supporting the association of any modifiable factor...with reduced risk of Alzheimer's disease." By "modifiable factor," the report means nutritional supplements, dietary factors, medications, social factors, economic factors, medical conditions, toxins, and other environmental exposures.
But perhaps we are looking at the problem the wrong way. In geriatrics, it's actually quite rare to find a single intervention that can prevent a complex condition, what geriatricians call a syndrome. A growing literature advocates a multi-pronged attack on this sort of problem. The risk of falling, for example, can be lowered somewhere between 25 and 39% of a combination of maneuvers, including review of medications and gait and balance training. The risk of developing delirium (an acute confusional state) in the hospital can be lowered by a third with a combination of 6 interventions, including avoidance of sleeping pills and providing patients with their glasses and hearing aids.
Maybe, just maybe, the risk of dementia can be lowered by maintaining contacts with other people, participating in social activities, playing music, exercising, and taking medication to treat high blood pressure. Each alone may have an extremely modest effect, but together, they just might make a difference.
Dementia is unfortunately a very common condition which more and more people are developing as the population ages. At last count, 5.4 million Americans had Alzheimer's disease. Medications to treat Alzheimer's are mediocre-the most positive statement the American Psychiatric Association could make in a recent practice guideline for the most effective drugs, the cholinesterase inhibitors, is that they have a "modest" effect in a "substantial minority" of patients. Hardly a ringing endorsement. The antipsychotics, drugs often prescribed to treat the behavioral manifestations of dementia, have been associated with a small increased risk of death-which might be an acceptable price to pay if they worked, but they rarely do. Despite the scientific progress in the understanding of how Alzheimer's disease develops-and we know infinitely more today than Alois Alzheimer did in 1906 when he peered through the microscope and found plaques and tangles outside and inside (respectively) the neurons of his former patient, Auguste D-the prognosis for effective intervention is poor.
The new NIH report is very blunt: "There is currently no evidence considered to be of even moderate scientific quality supporting the association of any modifiable factor...with reduced risk of Alzheimer's disease." By "modifiable factor," the report means nutritional supplements, dietary factors, medications, social factors, economic factors, medical conditions, toxins, and other environmental exposures.
But perhaps we are looking at the problem the wrong way. In geriatrics, it's actually quite rare to find a single intervention that can prevent a complex condition, what geriatricians call a syndrome. A growing literature advocates a multi-pronged attack on this sort of problem. The risk of falling, for example, can be lowered somewhere between 25 and 39% of a combination of maneuvers, including review of medications and gait and balance training. The risk of developing delirium (an acute confusional state) in the hospital can be lowered by a third with a combination of 6 interventions, including avoidance of sleeping pills and providing patients with their glasses and hearing aids.
Maybe, just maybe, the risk of dementia can be lowered by maintaining contacts with other people, participating in social activities, playing music, exercising, and taking medication to treat high blood pressure. Each alone may have an extremely modest effect, but together, they just might make a difference.
April 13, 2010
It’s the Law
After all the rancor and the political posturing and the delays, we finally have major health reform legislation. The new law will result in 30 million currently uninsured Americans buying health insurance and it will abolish some of the most egregious practices of the insurance industry, such as use of pre-existing conditions to refuse coverage. But what effect will it have on controlling the cost of medical care?
The rate of rise of health care costs is a problem, as Peter Orszag (formerly of the CBO and now director of the Office of Management and Budget); Rand Corporation researchers; and the conservative think tank, the Heritage Foundation, all agree because it is a major threat to the American economy. The long-term projections of the CBO, published last July, are that total U.S. spending on health care, which was 16% of GDP in 2007, will rise to 25% of GDP in 2025 and 37% of GDP in 2050. The new law has the potential to result in a significant decline in the percent of GDP we spend on health care each year. But whether it achieves this end depends on how several key provisions of the bill are actually implemented.
The provisions of the health reform legislation that could have a profound effect on the rate of growth of spending on medical care have to do with payment reform. And the potentially most potent payment reform strategy that appears in the bill is “bundling.” The legislation calls for the establishment of a national Medicare pilot program to “test, develop, and evaluate” bundled payment for acute inpatient hospital care, physician services, outpatient services, and post acute care for a single episode of care. According to estimates by researchers at Rand, a system of bundled payments, could potentially decrease national health spending by as much as 5.4% in the next 10 years (if applied to both Medicare and the private sector). The same researchers propose a 6.2% target for reducing spending on health care over the next 10 years; hence bundling alone could make an enormous difference.
The new law also provides incentives to health care systems to form “accountable care organizations” (essentially networks of providers that agree to capitation, another form of bundling) by offering them a share in the savings they generate for Medicare if they meet quality targets. It remains to be seen how widespread accountable care organizations will become. Health care reform also provides for an “Innovation Center” within CMS to evaluate, test, and expand different payment structures. Whether this provision will lead to savings depends on what payment structures are tested, how effective they are, and whether they are then disseminated. A final provision in the domain of payment reform is the establishment of an Independent Payment Advisory Board, charged with submitting legislative proposals to reduce the per capita rate of growth in Medicare spending whenever spending exceeds a target growth rate. However, the Board is prohibited from submitting proposals that will “ration care,” a provision, like the notorious “reasonable and necessary” language of the original Medicare statute, which will no doubt serve as the basis for rejecting any plan that restricts potentially useful treatment on the basis of cost.
Beyond payment reform, the new law will establish a Patient Centered Outcomes Research Institute to conduct research comparing the clinical effectiveness of alternative treatments. In principle, this kind of information could change medical practice to avoid the use of unnecessary or unnecessarily expensive treatments. But the bill has a built-in guarantee that the information will not be used in this way. It states that the findings of the Institute “may not be construed as mandates, guidelines, or recommendation for payment, coverage … or used to deny coverage.”
A powerful new law is on the books. With it, the U.S. finally joins all the other countries in the developed world in assuring a basic level of health care for its citizens. But will it constrain the rate of growth of spending on medical care? Only if we can depoliticize the boards, centers, and institutes that are the key to change.
A modified version of this article was posted on the Health Care Cost Monitor on March 19, 2010.
The rate of rise of health care costs is a problem, as Peter Orszag (formerly of the CBO and now director of the Office of Management and Budget); Rand Corporation researchers; and the conservative think tank, the Heritage Foundation, all agree because it is a major threat to the American economy. The long-term projections of the CBO, published last July, are that total U.S. spending on health care, which was 16% of GDP in 2007, will rise to 25% of GDP in 2025 and 37% of GDP in 2050. The new law has the potential to result in a significant decline in the percent of GDP we spend on health care each year. But whether it achieves this end depends on how several key provisions of the bill are actually implemented.
The provisions of the health reform legislation that could have a profound effect on the rate of growth of spending on medical care have to do with payment reform. And the potentially most potent payment reform strategy that appears in the bill is “bundling.” The legislation calls for the establishment of a national Medicare pilot program to “test, develop, and evaluate” bundled payment for acute inpatient hospital care, physician services, outpatient services, and post acute care for a single episode of care. According to estimates by researchers at Rand, a system of bundled payments, could potentially decrease national health spending by as much as 5.4% in the next 10 years (if applied to both Medicare and the private sector). The same researchers propose a 6.2% target for reducing spending on health care over the next 10 years; hence bundling alone could make an enormous difference.
The new law also provides incentives to health care systems to form “accountable care organizations” (essentially networks of providers that agree to capitation, another form of bundling) by offering them a share in the savings they generate for Medicare if they meet quality targets. It remains to be seen how widespread accountable care organizations will become. Health care reform also provides for an “Innovation Center” within CMS to evaluate, test, and expand different payment structures. Whether this provision will lead to savings depends on what payment structures are tested, how effective they are, and whether they are then disseminated. A final provision in the domain of payment reform is the establishment of an Independent Payment Advisory Board, charged with submitting legislative proposals to reduce the per capita rate of growth in Medicare spending whenever spending exceeds a target growth rate. However, the Board is prohibited from submitting proposals that will “ration care,” a provision, like the notorious “reasonable and necessary” language of the original Medicare statute, which will no doubt serve as the basis for rejecting any plan that restricts potentially useful treatment on the basis of cost.
Beyond payment reform, the new law will establish a Patient Centered Outcomes Research Institute to conduct research comparing the clinical effectiveness of alternative treatments. In principle, this kind of information could change medical practice to avoid the use of unnecessary or unnecessarily expensive treatments. But the bill has a built-in guarantee that the information will not be used in this way. It states that the findings of the Institute “may not be construed as mandates, guidelines, or recommendation for payment, coverage … or used to deny coverage.”
A powerful new law is on the books. With it, the U.S. finally joins all the other countries in the developed world in assuring a basic level of health care for its citizens. But will it constrain the rate of growth of spending on medical care? Only if we can depoliticize the boards, centers, and institutes that are the key to change.
A modified version of this article was posted on the Health Care Cost Monitor on March 19, 2010.
March 29, 2010
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