April 20, 2015

Helping the Other Half

There’s nothing much new in the latest edition of the Alzheimer’s Association Alzheimer’s Facts and Figures, which came out last month. Once again, the report documents that about 43% of people age 75-84 have Alzheimer’s. Since no more than 75% of all dementia cases are due to Alzheimer’s disease, that means that over half of  people in this age group have dementia of one kind or another.

The proportion varies depending on how dementia was assessed and on the ethnic, geographic, and gender composition of the people studied. But despite an enormous amount of effort and much progress in the domain of understanding the pathophysiology of Alzheimer’s disease, the Alzheimer’s Association reminds us that there is no drug available today that slows or stops the death or neurons that causes Alzheimer’s disease.

The federal government’s National Alzheimer’s Project Act and Obama’s BRAIN (Brain Research Through Advancing Innovative Neurotechnologies) initiative are redoubling the effort to find a cure. That would be terrific—though we should remember that the last concerted effort to wipe out a chronic disease, the War on Cancer, was launched in 1971 and is still being fought.

But what about the other half—those older people who don’t have dementia? Is there anything that medicine should be doing special for them?

A new report from the well-respected, non-governmental, non-profit Institute of Medicine released last week addresses this question. Entitled Cognitive Aging: Progress in Understanding and Opportunities for Actionthe report makes ten recommendations for collecting data, engaging in research, developing programs, and providing resources that seek to maximize cognitive function in older people who don’t have dementia. It’s an intriguing report, principally because it focuses on what is most important to older people and is the essence of geriatric medicine—function, rather than disease. The authors cite an AARP survey of members in which fully 87% identified “remaining sharp” as one of their major concerns. Older individuals and their families are concerned with optimizing mental performance. They are alarmed by the recently described disorder, “Mild Cognitive Impairment,” a condition that does not meet the criteria for dementia but affects the ability to function in day to day life, whether or not it progresses to full-blown dementia.

The study is also of interest because of it public health angle—it draws attention to the major societal consequences of age-related cognitive decline, things like traffic accidents (as people with impaired judgment or slow reflexes continue to drive) and financial fraud (resulting from impaired decision-making on the one hand and minimal consumer protections on the other). The recommendation to develop assessment tools, educational programs, and improved regulations, as well as alternative means of transportation, have the potential to maintain quality of life for older individuals and to lower costs.

The report makes common-sense suggestions for preventing age-related cognitive decline: being physically active, remaining socially and intellectually engaged and getting enough sleep. Unfortunately, there is no more evidence that these measures will maintain cognitive function than there is that they will prevent dementia. That is, they might help and they can’t hurt. But to suggest that they are proven to be effective is, alas, to overstate the case.

Despite succumbing to the temptation to offer a little bit of hype along with a lot of wisdom, the report’s authors make a valuable contribution by reminding us to pay attention to the other half. Its broad societal focus is welcome, as is the recognition that it is function rather than disease that matters most to the majority of people as they age.

April 12, 2015

What We Believe

Kudos to the Huffington Post for running an article about the new report from the FrameWorks Institute, “Gauging Aging: Mapping the Gaps Between Expert and Public Understandings of Aging in America.” And shame on the NY Times, the  Washington Post, the Wall Street Journal, and the other major newspapers in America for ignoring it. That’s not entirely surprising since the report is all about the disconnect between public perception and reality, and the media are to a large extent responsible for shaping popular understanding.

The new study does not report the results of an opinion poll. It is not based on trendy focus group analysis. It seeks to understand what both geriatric experts and the lay public believe about aging and the “assumptions and thought processes” that underlie their opinions. The authors, supported by funding from AARP and a variety of foundations including the John A Hartford Foundation and the Retirement Research Foundation, use a “cultural-cognitive approach” to their work. That means they probe, they explore, they question. They do not rely on “big data.”

So what did they find? They learned a great deal about the gaps between the scientific understanding of aging (by which I mean physiologic, medical, psychological, and sociologic) and the public’s view. They learned so much that I will just touch on some of the highlights here.

Attitudes toward aging: the experts see aging as presenting challenges, but also an opportunity for growth and the possibility of continued contributions to society. The public sees aging as the enemy, to be combatted rather than embraced or supported. In particular, aging is thought to bring with it decay and disability; in fact, older people are very heterogeneous.

Root cause of aging: Americans tend to believe that what happens to them is entirely within their control. If they eat right, exercise, and lead a virtuous life, they can avoid the aging process entirely. The truth is more nuanced, with both genetic and external factors playing a significant role. In a similar vein, the public tends to believe that if older people do become disabled or demented and cannot take care of themselves, then their family rather than the government has an obligation towards them.

What we need in order to age well: The experts see a need to create structures to facilitate older engagement—whether opportunities for part time work, better transportation, or more volunteer positions. A related theme is the need, recognized by experts, for new public policy initiatives to modify today’s reality. The public, by contrast, takes the status quo for granted and assumes it’s up to older people to avail themselves of existing options.

There’s more. Maybe I will write more about this subject next week. Better yet, just read the study. And I look forward to future work from the FrameWorks Institute addressing how to change popular perceptions. Maybe they will shed some light on how to modify the public view of climate change and evolution, too.

April 05, 2015

Chemotherapy for Alzheimer's?

A provocative opinion piece in JAMA Neurology offers new hope for the treatment of Alzheimer’s disease. University of California Santa Barbara neuroscientist Kenneth Kosik begins by acknowledging that recent drug trials have all failed, this despite the fact that that were designed based on the latest understanding of the pathophysiology of Alzheimer’s disease. The most spectacular recent failures were studies of two separate monoclonal antibodies that were expected to selectively attack amyloid deposition in the brain. This approach was so intriguing that scientists haven’t given up on it yet, despite the lack of success so far—just a few weeks ago the drug company Biogen announced the results of a Phase I trial of yet another monoclonal antibody, this one evidently quite promising. But Kosik has a different idea.

Kosik comments that the typical response to the drug trial failures is either to question whether our understanding of the mechanism by which Alzheimer’s is produced is correct or to conclude that treatment of the disease will need to begin before symptoms develop. He suggests that perhaps where we have gone wrong is in believing that Alzheimer’s disease is homogeneous. In fact, he argues, there are many genetic variants. The best known is the APOE alleles, with the APOE4 allele conferring particularly high risk. And of course there are the relatively rare familial forms of Alzheimer’s disease, which involve mutations in any of several chromosomes. Perhaps if we identify a person’s genome, we can find a particular therapy that will work for that person.

This is the approach that is increasingly used in the treatment of cancer, with a handful of notable successes. In non-small cell lung cancer, for example, there are several mutations typically found in younger patients with no history of smoking. Drugs targeted against these mutations have produced excellent results in patients with the relevant mutation: the drugs Erlotinib (Tarceva) and Crizotinib (Xalkori), when used in appropriate patients, can convert what was previously a uniformly lethal disease (usually within a year) into a chronic illness. Will the same strategy work for Alzheimer’s disease?

Maybe. It’s certainly worth pursuing. And Kosik also has ideas about how to proceed with this kind of targeted, individualized treatment—he recommends what are known as “N of 1 trials,” tests of a potentially useful drug in a single patient rather than the conventional strategy of testing a drug in a large group of people. The proposed strategy would both revolutionize the treatment of a particular disease (Alzheimer’s) and change the search process for new drugs. It’s not likely to change the epidemiologic reality any time soon, but it’s more promising than many radical new ideas. Let's hope NIH or other funding agencies have the wisdom to provide the support needed for this innovative work to go forward.

March 30, 2015

When Push Comes to Shove?

There’s been a lot of talk about advance care planning lately, with Ellen Goodman’s Conversation Project, Atul Gawande’s book, Being Mortal, and very recently, Angelo Volandes’ book, The Conversation. The message: think about what matters to you and discuss with your physician and with your family the approach to medical care that makes sense for you if you become very ill. We know that these kinds of discussions may not lead to the patient’s directive being followed when he or she actually does get very sick—sometimes the advance directive does not travel with the patient to the hospital, often the directive is difficult to interpret in practice (what exactly does “no heroic measures” mean?), and in some circumstances physicians or families override the directive. We know that patients with a medical order such as a POLST (Physician Orders for Life-Sustaining Treatment) are more likely to get what they signed up for than those with a wish statement (for example a living will). What we don’t know much about is whether patients change their minds when faced with an actual illness. A new study examines how often patients admitted to an ICU with some kind of “treatment limitation” in effect nonetheless received the treatment they previously had said they didn’t want.

The answer: about one-quarter of the time.The most common treatment that people specifically said on admission to the hospital they didn’t want was attempted CPR (accounting for 77.4% of the limitations expressed), but 24.6% of them ended up having CPR initiated. Another 21.3% of people said they didn’t want specific therapies such as dialysis or artificial nutrition, but it is not clear from the study just what proportion of them received those treatments. Finally, 3.9% of those admitted said they wanted a focus on comfort. We don’t know what kind of treatment those patients in particular received. All we know is that of the 13,405 patients admitted to one of 141 ICUs at 105 US hospitals between 2001 and 2008 with some kind of treatment limitation request in place, 3123 ended up getting attempted CPR, 3841 got intravenous medicines to maintain their blood pressure, 2660 were put on breathing machines, and 283 got dialysis. Finally, we know that there was considerable variability between hospitals, both with respect to the rate of treatment limitation expressed initially (from 1% to 30%) and to the rate of treatment limitation reversal (2% to 76%). So what does this all this mean?

Since we don’t know what led to the changes that occurred, we can’t know for sure. What is clear that these were not cases where the doctors simply never saw the advance directive. These are all cases in which the plan was not to provide a specific treatment (principally CPR) but the reality was that the order was rescinded and the forbidden treatment was actually administered. So somewhere between entering the ICU and leaving it (whether alive or dead), a major change took place. It could be that when push came to shove, patients changed their minds. When confronted with their own mortality, they chose to have a shot, however small, at living longer. It could be that most of the patients were incapacitated by illness and the actual decision to reverse course was made by a health care proxy or family member—we know from other studies that fully 70% of patients in whom a decision about life-sustaining treatment needs to be made are cognitively unable to engage in decision-making at the crucial moment. It might be that the limitation-of-treatment directive didn’t really reflect the patient’s goals—perhaps what they meant was they didn’t want to spend their life as a vegetable, not that they didn’t want a trial of life-prolonging treatment—and they came to understand that their directive as written should be revised.  Or it could be that patients and families were persuaded to change course because the environment of the ICU promotes life-prolonging treatment and it is very difficult to stick to a plan of care that violates the raison d'etre of the ICU. 

In all likelihood, the answer is all of the above. This study does not imply we should abandon advance care planning. It’s worth pointing out that 75% of patients with treatment limitations in place retained those restrictions. But it does raise questions about whether patients really know what they are signing when they complete an advance directive—whether a traditional living will, a detailed instructional directive, or a POLST form. It makes me even more convinced than ever that we need to focus more strongly on ascertaining the patient’s goals of care when we engage in advance care planning, and leave the translation of those goals into medical treatment to the moment when an actual decision must be made. And it does remind us that hospital culture in general and ICU culture in particular are very powerful. When an institution is structured and staffed to provide life-sustaining care, then treating some patients without using life-sustaining care creates cognitive dissonance. If patients truly want a different approach to care, we should provide an alternative environment in which to deliver that care, either the home or an intermediate facility such as a skilled nursing facility.

March 22, 2015

Putting the Genie Back in the Bottle

You can’t put the toothpaste back in the tube. You can’t put the genie back in the bottle. You can’t turn back the clock. We have lots of expressions denoting the irreversibility of certain actions. Getting patients to stop taking a particular medication or to abandon a procedure—and persuading doctors to stop prescribing it—seems to be in the same camp. Unless something comes along that’s much better, or at least that the pharmaceutical or device manufacturing company says is much better, we are extremely reluctant to change. A series of articles in JAMA Internal Medicine
discuss this phenomenon, calling it “the undiffusion of established practices.”

One article reports that physicians gradually adopted the practice of tight control of blood sugars in the ICU after a single study showed that patients did better when their blood sugars were as close to normal as possible, but then abruptly gave up the practice after a later study drew the opposite conclusion. A second article describes how physicians jumped on the bandwagon of ordering noninvasive  screening for coronary disease in patients scheduled for non-cardiac surgery, only to discover later that the screening was not beneficial—and the routine use of such testing decreased. A third article discloses that professional medical societies tend to continue to support practices that have been challenged or even debunked if their members believe the practices to be useful.

What does all this tell us about “undiffusion?”  How do we change behavior? One answer is that we should move slowly to adopt something new, whether a medication, a procedure, or a process. We should exercise caution, given the reality that the best new thing often turns out not to be the best. A second answer is to design studies that are better at looking for subgroups that may benefit from a new approach—even if the approach doesn’t make sense for everyone. But I think there’s a lot more to be said about putting the genie back in the bottle, particularly as we begin to recognize that less may be more.

It’s instructive to look at the cases where the genie did go back in the bottle and compare them to the cases in which he didn’t. Consider, for example, the process of tightly controlling blood sugars in the ICU, a practice that physicians readily abandoned. What’s striking about this is that controlling blood sugars very tightly is a nuisance—it means checking the blood sugar four times a day and adjusting insulin doses every time. That’s labor intensive—someone has to do the tests and someone else has to respond to the results. And there’s nothing sexy about pricking a patient’s finger to get a drop of blood. It’s not nearly as exciting as seeing the patient’s organs in color on a CT-scan image—a test that was not so readily abandoned. Finally, there’s no drug company or device manufacturer that stands to gain from widespread use of fingersticks, though there is from diffusion of 128-slice CT scanners, not to mention 256-slice machines.

What about the recent example in which use of antidepressants in young people decreased after the FDA issued a black box warning about potential side effects? Some critics argue that in this instance, putting the toothpaste back in the tube was wrong-headed: many more people suffered from not being treated than from the side-effects of treatment. Whether or not it was a good idea to cut back on antidepressant use, the major driver of the behavioral change appears to have been the media. Newspapers reported that antidepressants were bad; they were dangerous; they killed people. They presented a far less nuanced picture than the original article. But the combination of publicity and fear-mongering was effective and antidepressant prescribing rates fell significantly.

Finally, the most dramatic, if obvious, examples of turning back the clock occur when the FDA orders a drug company to recall its drug. When Vioxx was taken off the market, after revelations that it significantly increased the risk of heart attacks, use of Vioxx plummeted. In a similar vein, when health insurance companies decide not to pay for something, use generally falls. Bone marrow transplantation for the treatment of metastatic breast cancer ceased when, based on revelations that an earlier study had been fraudulent, coverage was halted.

Going back is hard. Commenting on the articles in JAMA Internal Medicine, Frank Davidoff quotes David Hume: “Men generally fix their affections more on what they are possessed of, than on what they never enjoyed. For this reason, it would be greater cruelty to dispossess a man of any thing, than not to give it to him.” Likewise, research in cognitive psychology confirms that people are far more distressed by what they perceive to be losses than they are ecstatic about what they see as gains. So reversing course is likely to require a multi-pronged approach. We need to have more solid evidence to adopt change in the first place and we should be looking more carefully at subgroups of the population when we draw our initial inferences about efficacy and we need more measured and judicious reporting by the news media and we need to use the nuclear option—removing ineffective or harmful interventions from the market or from third party coverage. Only then will we gain control over the phenomenon of persistent use of established but suboptimal treatment.

March 19, 2015

You Can't Put the Toothpaste Back in the Tube

Why is it so hard to get people to stop taking medications--even if they're shown not to work? See forthcoming blog post.

March 15, 2015

No Quick Fix for Mortality

Quercetin hit the airwaves this week, when the media reported that scientists have found "a new class of drugs that dramatically increases healthy lifespan.” Not to be confused with Coenzyme Q10, another naturally occurring compounded touted as an antioxidant that delays aging, Quercetin is a “natural compound” sold in health food stores as an anti-inflammatory agent. But now it is has been dubbed a “senolytic,” a drug that slows aging by alleviating symptoms of frailty, improving cardiac function, and extending a healthy lifespan. Sounds great. But before you rush to buy some, lets look at the evidence.

The article on which this promising claim is based is a highly technical paper in the journal Aging Cell entitled, “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” The authors argue that aging is due in large part to cellular senescence, which in turn means the process by which cells lose the capacity to grow. These senescent cells secrete all kinds of chemicals that are hypothesized to produce decline and death. But not all the cells in an organism become senescent at once. In fact, only 15% of the cells of very old primates are “senescent.” The idea is to kill off these senescent cells, thus preventing them from making those disease-making chemicals. 

It turns out that a variety of drugs, all belonging to this new class of “senolytics,” selectively kill senescent cells. And indeed, when a combination of two drugs, a known cancer drug and the compound Quercetin, were given to old mice, they lived longer and had lower rates of “age-related symptoms and pathology” compared to old mice that didn’t get the cocktail. The two drugs worked especially well together, but each drug alone was effective. So where’s the rub? Why not rush out and buy some Quercetin, which is available now and without a prescription?

It’s not that Quercetin might be harmful. The FDA has studied the compound and determined that it has no significant toxicity because it is destroyed in the intestinal tract--before it can even get into the bloodstream. So while the drug might in principle do something if given intravenously, taking the currently available formulation won’t. Parenthetically, you certainly don’t want to buy some Dasatinib either, the other drug used in the study. Dasatinib is a “targeted chemotherapy” drug, used to treat the relatively rare blood cancer, Chronic Myelogenous Leukemia (CML), when the preferred drug, Gleevec, stops working. It costs roughly $10,000 for a thirty-day supply. It is approved only for use in blood cancers, though in principle it could be prescribed off- label for other non-proven indications.

Another reason for holding off on your Quercetin purchase is that its effectiveness has been demonstrated only in rodents. Using mice to explore the genetic underpinnings of mortality has a venerable history: the gerontologist David Sinclair, for example, has been using a mouse model to study Sirtuin genes, genes that appear to protect against aging. He has discovered "sirtuin-activating compounds," small molecules that decrease frailty--in mice. These frail mice exhibit muscle weakness, they get heart disease, and they die earlier than their non-frail counterparts. But whether frail mice are truly analogous to humans, in whom frailty entails heightened vulnerability to stressors, and in whom frailty translates into an increased risk of falls, delirium, and disability, is another matter.

The main reason for skepticism about the latest claims about an immortality pill goes back to the article written by Olshansky, Hayflick and Carnes in 2002 and republished by Scientific American in 2008 that debunks all claims to have discovered the fountain of youth. These scientists take seriously the desire to promote healthy aging. They see the virtue in postponing the aging process altogether rather than tackling the diseases of old age one at a time: if aging is a zero-sum game, then curing cancer, for instance, would simply mean that more people will die of Alzheimer’s disease. But they are horrified by the amount of money desperate people spend on anti-aging products that are no more likely to be beneficial and just as apt to be harmful as many of the quack nostrums of the nineteenth century.

Today, a number of companies are peddling “anti-aging” drugs. Elysium, cofounded by Lenny Guarante of MIT (David Sinclair’s mentor), makes “Basis,” a mixture of nicotinamide and pterostilbene (an anti-oxidant), which it sells on line. Even Novartis, a major drug manufacturer, is trying to get into the anti-aging market with rapamycin, as Bloomberg News reported with enthusiasm.

None of these drugs has been proven to work. Some may be harmful. All are costly. It's not necessary to discuss  the ethical concerns about trying to lengthen the human lifespan to have an opinion about Quercetin. It's an interesting chemical for scientists to study in the laboratory, but it's not ready for prime time.

March 08, 2015

Getting to Yes?

Last fall, the prestigious Institute of Medicine released a “discussion paper” supporting the use of shared decision to improve outcomes in medicine. It specifically advocated greater use of decision aids, formal algorithms (written, oral, or video) to facilitate the process. Shared decision-making is not a new concept: the term itself was used and the practice recommended in 1982 when the President’s Ethics Commission (the full name is the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research) issued a lengthy report on decision-making in medicine. What's fascinating is that the New England Journal of Medicine could feature an article called “Enduring and Emerging Challenges of Informed Consent” that makes only a passing reference to shared decision-making. How is informed consent related to shared decision-making (SDM)?

Both shared decision-making and informed consent are supposed to be prerequisites to any decision about medical treatment. In the SDM approach, clinicians share information with patients about the potential risks and benefits of possible treatment options (or testing or screening); patients explore with clinicians their preferences; and through a process of deliberation, they reach a mutual decision. In the informed consent approach, clinicians recommend a particular treatment, summarize its risks and benefits in the context of available alternatives, and patients either accept or reject the clinician’s proposal.

The two models overlap a great deal—both involve presenting information and both hinge on patients’ understanding their options and making an un-coerced choice. But there are also stark differences. Informed consent is all about “getting to yes;” the clinician has decided what’s best for the patient (perhaps but not necessarily based on a prior conversation), though the patient is free to decline. It is a very legalistic process, whose centerpiece is a form in which a patient officially agrees to the treatment, sometimes signing away all liability on the part of the clinician. Shared decision-making is all about enabling patients to choose their own healthcare.

What’s striking is how separate the literature on these two subjects is today, as the IOM report and the NEJM article attest. The topics are like descendants of a common ancestor that diverged in their development 50 years ago. Lawyers and surgeons focus more on informed consent; ethicists and internists on shared decision-making. But there is little justification for two separate processes. 

Far more reasonable would be a single process that begins with physicians describing to patients their general health status and the likely course of any new condition that warrants treatment; the process would then move to patients indicating their goals of care; next, physicians would explain how to translate those goals into a treatment, describing the risks of pursuing the proposed strategy. Based on this give and take, physicians recommend a treatment, patients accept or reject the treatment, and then both parties sign a document indicating their conclusion and briefly describing the process by which they reached that decision. For some kinds of treatment, for instance those well-established therapies for which there are no viable alternatives (eg surgery for a mobile patient with a hip fracture), the first few steps would go very quickly. For other kinds of treatment, for example those with multiple alternatives (eg chemotherapy, radiation, or hospice for a patient with advanced cancer), all steps of the process would be followed and documented.

Only a standardized, consistent approach to decision-making can achieve the aims of both SDM and informed consent: knowledgeable, thoughtful patients participating meaningfully in their own healthcare.

March 01, 2015

The Age-Cost Connection

It’s been well known for a long time that the amount Medicare spends on patient care every year increases with age. That’s not entirely surprising—after all, 80-year-olds are in general less healthy than 70-year-olds, so they need and receive more medical care. But is there an age when per capita spending stops going up, or even falls? If you think there is, guess what age that happens. Why? What would cause spending to level off? A recent article in Health Affairs gives some of the answers, at least about the facts.

Examining Medicare data from 2000 to 2011 for fee-for-service beneficiaries, the authors confirm that as recently as 2011, Medicare per capita spending rose with age, peaking at age 96 and then gradually declining. Spending for 96-year-olds averaged $15,145 compared to less than half that, or $7566, for 70-year-olds. What’s really fascinating is that in 2000, the age at which Medicare per capita spending peaked was 92, and it’s been steadily increasing ever since.

Before we can speculate about why, we need to understand what the money is being spent on. The study answers this question as well. For nonagenarians, much of the spending goes to skilled nursing facilities (that doesn’t mean long stay nursing homes, which aren’t covered by Medicare, but rather short term, post-acute or rehabilitative care). This finding doesn’t imply that hospital spending goes down; on the contrary, spending on inpatient hospital services remains a relatively constant share of per capita spending until patients reach their late 90s.

Translation: older people use a lot of medical services. They use more and more until they are close to 100 and that includes hospital care, along with hospice and skilled nursing facility care. Evidently our view of what constitutes reasonably treatment has been shifting over time—we used to think that it was all right to treat octogenerians aggressively, but we drew the line at nonagenerians. Now we’re treating nonagenarians aggressively and drawing the line at centenarians.

There is one bit of promising news, one hint that at least some patients and doctors are thinking twice about subjecting the oldest and frailest to all the technology we can muster. If we look at per capita spending the year people die, we find that Medicare spent $43,000 on 70-year-olds but only $20,000 on centenarians. The difference was due almost entirely to a disparity in hospital use. Apparently, it’s easier to recognize or perhaps to accept that a 100-year-old is dying, and to tailor treatment accordingly, than to accept that a 70- or even a 90-year-old is dying. But once we do acknowledge the inevitable, we restrain our impulse to try to prolong life, whatever the cost both to individual dignity and to the nation’s pocketbook.

Maybe, just maybe, we will come to accept that there is a price to pay for invasive treatment even when death is not quite so imminent, and that a different kind of treatment may be more humane for those who are physically frail or demented, regardless of age.