Three Strikes and You're Out

Three times, Eli Lilly has tried to demonstrate the efficacy of the drug solanezumab in the treatment of Alzheimer’s disease. And three times, the drug failed. What does this mean?

Solanezumab is a monoclonal antibody that selectively attaches to a form of amyloid-beta, widely thought to be the key agent that causes Alzheimer’s disease. The first two studies were phase three, double-blind studies of patients with mild to moderate Alzheimer’s disease. That means earlier studies had found the drug reasonably safe and had identified a dose that had the desired effect on brain amyloid. The results of EXPEDITION1  and EXPEDITION 2 were both published in the New England Journal of Medicine in January, 2014. The authors found that after 18 months of treatment with intravenous solanezumab, there was no improvement in either tests of cognitive function (the Alzheimer’s Disease Assessment Scale) or daily activities (the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale). There was a hint in subgroup analysis that maybe the patients with milder disease might benefit; hence the new study, EXPEDITION3, which evaluated the drug in patients with clinical evidence of mild dementia and abnormalities on PET scan suggestive of amyloid deposition. But alas, the results of this trial are no more encouraging than those of its predecessors.

Solanezumab is not the only anti-amyloid monoclonal antibody that has been tested and found wanting. Two other double blind randomized, placebo-controlled phase 3 trials were conducted with Bapineuzumab in patients with mild to moderate Alzheimer’s, One trial involved carriers of the APOE-4 allele, a gene for a cholesterol carrying protein that has been associated with an increased risk of dementia; the other involved non-carriers. Once again, there was no difference between patients receiving active drug and those getting placebo, whether on tests of cognition or on measures of overall daily functioning.

So now solanezumab has failed three times. Not because it caused terrible side effects, as was the case with earlier attempts to “vaccinate” against Alzheimer’s disease, that were in some instances effective but that caused a debilitating and/or lethal inflammatory response in the central nervous system. Solanezumab failed because it didn’t work. What does this tell us about the use of monoclonal antibodies in Alzheimer’s disease?

An article in Scientific American two years ago on “Why Alzheimer’s Drugs Keep Failing” makes clear that it’s not just a handful of drugs that have fallen short of their promise. According to the article, “dementia has become a graveyard for a large number of promising drugs.” In fact, the failure rate for Alzheimer’s disease “drug candidates” is 99.6 percent (compared to 81 percent for cancer drugs). The problem, in large measure, is that symptoms begin a decade or more after the disease actually starts, by which time intervention may be too late. It’s as though we didn’t treat coronary artery disease until after a patient developed cardiomyopathy, until after so much heart muscle had died that the heart scarcely pumped at all. One strategy for drug development is therefore to identify markers for disease long before there are clinical manifestations, in principle allowing for treatment at a much earlier stage than occurred with any of the solanezumab trials. Another is to target other suspects besides amyloid—abnormal proteins such as tau that also contribute to the development of dementia. Still another strategy is to focus on “disease-modifying treatment,” an approach that slows the progression of the disease rather than one that focuses on cure.

Perhaps another reason that Alzheimer’s disease is such a hard nut to crack is that the brain is an extraordinarily complicated organ, arguably far more complex than the heart. The heart, after all, is basically a pump. An ingenious pump fed by a system of blood vessels and operated by an electrical mechanism, and one that has proved far more complicated than was initially assumed, but nonetheless simple by comparison with the brain. Because the brain is such a remarkable organ and because Alzheimer’s disease strikes its most elusive function, cognition, it is not entirely surprising that treating this disorder has proved so challenging.

The message is not that we should give up. But it is that there’s no cure around the corner. The most effective strategy to date is to decrease the likelihood of developing Alzheimer’s through a combination of smoking cessation, treatment of high blood pressure, and treatment (or prevention) of diabetes—a strategy developed for the prevention of cardiac disease and incidentally found to help stave off dementia. And in the mean time, as scientists continue to struggle to understand the pathogenesis of Alzheimer’s and devise new strategies for intervening in the relentless progression of this dread disease, we must continue to find better ways to support people who are afflicted, allowing them to find as much meaning and satisfaction as possible in their lives.

This is the last post on “Life in the End Zone” in 2016. See you next year!

Antipsychotics: Use as Directed

Antipsychotic medication is effective for people who are psychotic—period. It’s been used for other conditions, such as the behavioral symptoms of dementia, and it turned out not to work. It’s been used for delirium, a type of confusion that often arises in older people or people nearing the end of life, especially in the hospital, and many doctors swear it’s the only medication that helps this distressing and dangerous disorder. But a new study from Australia suggests that antipsychotic medication doesn’t work for delirium either. 

The specific situation the Australian doctors looked at was delirium in the setting of patients with advanced illness, either patients on an inpatient palliative care service or patients enrolled in a hospice facility. Out of well over 1000 patients with delirium, they were able to identify 247 who were both eligible and willing to enter the study. This group, with a mean age of 75, were randomized to risperidone (a commonly used antipsychotic), haloperidol (another commonly used antipsychotic), or placebo. Patients were also given unspecified non-medicinal treatment, presumably things like a sitter (someone to stay with them) or relaxation techniques such as massage. They were also given subcutaneous midazolam, a very short acting anti-anxiety medication under the skin, for extreme agitation. The results? Patients receiving either risperidone or haloperidol had more severe symptoms of delirium than those treated with placebo. They also, not surprisingly, had more Parkinsonian symptoms, the main side effect of these antipsychotic medications, and were more likely to die.

This is a disturbing result. Not only did antipsychotics fail to help, but they also seemed to make matters worse. Now maybe there’s something different about Australians, or maybe the specific environment they were in—a palliative care service or hospice, though neither is clearly described—makes generalization to the American general hospital impossible. Or maybe people with delirium and advanced illness are somehow different from people with delirium who don’t have an advanced illness. And conceivably, other antipsychotics such as quetiapine or olanzapine are different. More likely, antipsychotics are simply a bad choice in the treatment of delirium.

Antipsychotic medications are remarkable medications—for the treatment of psychosis in psychiatric conditions such as schizophrenia and bipolar disorder. But maybe we should stop using them for anything other than these indications.

Something to be Thankful For

Back in February, I wrote that “some news is good news.” The news in question came from the Framingham study and it showed that the incidence of dementia had been falling in the US by 20 percent each decade since the 1980s. However, I was concerned about the generalizability of the finding since the total number of people identified as having dementia was 371—and they were all from Framingham, MA. Now another, larger study points to a similar decrease. That’s something to be grateful for this Thanksgiving season. 

Before we get too excited—or complacent—let’s consider a few caveats. The new study was based on data from the Health and Retirement Study, a large, nationally representative cohort study that’s been going on since 1992. It looked at the prevalence of dementia in all those in their survey who were over age 65 and lived either in the community or a nursing home in one or both of two sample years, 2000 and 2012. That turned out to be 21,057 people, of whom a total of about 2000 developed dementia. So far, so good: a bigger sample, drawn from the entire country, with a respectable sized group of individuals with dementia. 

But now for the problems. Dementia was diagnosed using a modified version of the Telephone Interview on Cognitive Status, a measure involving a 27-point scale. Sounds good, except that the full Telephone Interview on Cognitive Status is not an established way to diagnose dementia, and the abridged version used by the investigators is even less well established. And indeed, when compared to a different test which the authors regard as the gold standard, the telephone interview correctly classified dementia in 78 percent of respondents. The other 22 percent of people were either falsely diagnosed as having dementia or incorrectly assessed as normal. That’s worrisome. The point of the study was to compare the prevalence of dementia in 2000 and 2012, which is awfully difficult to do if you can’t accurately determine prevalence.

Still, the findings of a decline in prevalence from 11.6 percent in 2000 to 8.6 percent in 2012 (corrected for the change in age and sex distribution of the population) are consistent with those of the Framingham Heart Study and of a British study. They show a 24 percent decline in prevalence of the disease, despite an increase in obesity and diabetes during the same period. And, as with the earlier studies, increases in education and improvement in control of cardiovascular risk factors (high blood pressure, smoking, and diabetes) are associated with the fall in dementia.

So maybe it’s really true. Maybe the risk for each us individually is not quite as bleak as I have been suggesting in this blog. On the other hand, the projection is that by 2050, there will be 83.7 million people age 65 or older. If even 8.6 percent of them have dementia, as suggested in the current study, that’s over 7 million people. Unless we find a cure soon, which doesn’t seem terribly likely, we’re still going to be faced with an enormous public health problem.  

It's the Social Stuff, Stupid

Health care policy mavens are finally recognizing that we need to do a better job taking care of the sickest and costliest patients in American society. These are people on whom we spend a large percentage of our health care dollars without much to show for it, either in terms of standard health care outcomes or quality of life. Many of them have advanced illness. Many have multiple chronic diseases plus functional impairment plus extensive social needs. They’ve gotten the attention of people like David Blumenthal, who published an article called “Caring for High-Need, High-Cost Patients—An Urgent Priority” in the New England Journal in September and another article in JAMA sounding a similar call to action a few weeks later. They are the focus of the Coalition to Transform Advanced Illness, which produced a white paper mapping out a strategy for care and which just held a National Summit on Advanced Illness Care. Everyone defines the relevant population slightly differently and everyone makes somewhat different proposals for moving forward. One of the most creative is an idea that has been tried in England with good results.

This model gives high need patients a personal health care budget. The budget is determined by negotiation between the patient and the health care team. It “relies on a goal-setting and care-planning process in which patients and health care teams consider medical and social needs.” The budget allows payment for home supports and for technology that facilitates their remaining at home. It includes coverage for unusual and somewhat controversial non-medical needs such as a garden shed for someone with dementia so he could stay home because he had something to keep him occupied—the alternative was for him to become agitated and restless and quite likely require sedation and/or institutionalization. Interestingly, the budgets exclude access to primary care and hospital care, which are uncapped. Studies to date have found the system cost effective and associated with enhanced quality of life for the participants.

The result is not entirely surprising in light of the pioneering work done by Elizabeth Bradley and Lauren Taylor, popularized in a NY Times article in 2011 (and recently the subject of a book, The American Health Care Paradox.) What these researchers found was that though the US spends as much as 50% more than other developed countries on acute hospital care, imaging studies, lab tests, and other standard medical care, it spends much less than most other OECD countries on social services including old age pensions, disability, family support, and housing. If you combine the expenditures on both health and social services to give the true per capita spending in each country (with the amounts adjusted for GDP), it becomes clear why American health outcomes are so often inferior to those achieved in other countries: our total per capita spending is actually less than that of similar countries. The US over-invests in medical care and under-invests in social services.

A personal health budget that allows individuals to buy social services and other not strictly medical items that have the potential to enhance the coordination of care—a smart phone or a laptop, for example—is a way to compensate for America’s weakness. It fits into the prevailing ethos of individual control and of having “skin in the game.” 

If dressed up in sufficiently capitalistic sounding language, the proposal might even pass muster in a Republican-controlled federal government. It could finally transform care for the sickest, most vulnerable patients in the US health care system--and save money, too.

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Medicare and the Election

Today is Election Day. The choice is stark. And it’s not just a matter of choosing a knowledgeable, capable, and rational, although flawed Democratic candidate over an ignorant, incompetent, bombastic narcissistic Republican candidate. The election matters for health issues and older people as well. Here’s how.

The Trump and Ryan plans call for a repeal of the ACA. That means more uninsured people who will be sicker and costlier to care for once they become Medicare eligible.  That’s bad for those individuals and it is bad for Medicare. Trump and Ryan want to permit interstate sales of health insurance, which they think will create more competition and bring down costs. They don’t seem to understand that regional insurers don’t want to expand nationally: they have to negotiate contracts and rates with the hospitals in every state whose market they enter. Health insurance is not the same kind of commodity as furniture. That goes for Medicare Advantage plans along with private plans for those under age 65. Trump and Ryan want to expand the use of health savings accounts—potentially to Medicare patients. These high deductible plans encourage people to make foolish decisions about their health. Moreover, they affect the first few thousand dollars of health care expenses—enough to make a difference to people with limited incomes, but of no consequence for the most expensive parts of the health care system, namely hospital care.

Clinton and the Democrats would make insurance coverage more affordable by increasing tax credits for low income households. That means fewer uninsured people who will be sicker and costlier to care for once they become Medicare eligible. Families USA wants to add dental coverage to all public and private health plans—the one big gap in coverage for older individuals, even though poor dentition has been associated with pneumonia, nutritional problems, and other disorders. Clinton et al favor Medicare negotiating drug prices with manufacturers, potentially controlling one of the major contributors to out of pocket spending among older people.

For a more detailed analysis of “the choices on health reform in the US presidential and congressional elections” that doesn’t focus on older people, see the viewpoint piece in today’s JAMA Internal Medicine. 

Go out and vote! It matters, for Medicare along with so much else.

V is for Value

Ten years ago, Michael Porter, a professor at Harvard Business School, began shaking up the health policy world when he published, together with his colleague Elizabeth Teisberg, the book Redefining Health Care: Value-Based Competition. The concept became the official mantra of the American health policy establishment in 2010, when Porter summarized his ideas in the New England Journal of Medicine, asserting: “Achieving high value for patients must become the overarching goal of health care delivery, with value defined as the health outcomes achieved per dollar spent. This goal is what matters for patients and unites the interests of all actors in the system. If value improves, patients, payers, providers, and suppliers can all benefit while the economic sustainability of the health care system increases.”

Over time, this has been taken to imply the necessity for “value-based payment,” or VBP, also known as "pay for performance" (PFP). Just how pervasive this thinking is can be seen in a series of editorials published in JAMA and taken from the National Academy of Medicine’s “Vital Directions.” From the piece called “Tailoring Complex Care Management for High-Need, High-Cost Patients,” to the piece on “Improving Benefit Design to Promote Effective, Efficient, andAffordable Care,” VBP is assumed to be the answer. Even the article on “Preparing for Better Health and Health Care for an Aging Population” sneaks in mention of VBP. But will a reimbursement scheme that rewards “high value” care more than “low value care,” and presumably somewhat more than care that is somewhere between “high” and “low” on the value spectrum, really solve the problems of today’s health care system?

Underlying the fervent belief in the value of value is the assumption that in the bad old days—and still today in many places—when physicians and hospitals were reimbursed for the volume of services, it was this system that created over-use. Of course doctors order too many tests and prefer expensive procedures over cheaper ones, according to this reasoning, because what drives their behavior is reimbursement. It was the payment system that created the monster in the first place, and it’s the payment system that must be reformed today. But is this an accurate description of why tests and medicines and procedures are over-used today, let alone a plausible explanation of how the status quo arose in the first place? Isn’t it at least possible that the economists have it backwards—that the payment system reflected prevailing practice?

The trouble with the current ideological insistence that VBP is The Answer, aside from the fact that supposedly value-based reimbursement systems haven’t so far produced the desired result, is that it totally discounts the role of culture, of advertising, of popular expectations. When a physician orders an expensive test instead of relying on a cheaper one or, God forbid, on history and physical exam, maybe the reason is that the patient expects and wants the test—and may even be willing to pay a little extra to get it. Perhaps the physician, too, believes the expensive test is superior to the alternatives and doesn’t believe the calculation of “outcomes per dollar spent” accurately reflects the true value of the test. Perhaps the physician has been barraged with "information" by the producer of the machine used to perform the test and has come to accept the evidence and arguments of the device manufacturer as legitimate. Maybe the members of the group practice in which the physician works are collectively persuaded by the claims of the medical device industry. Maybe the physician gained experience with a particular type of device during residency and prefers this one, even though it is more expensive, because he is convinced that the outcomes in his hands will be superior if he uses the familiar equipment. Physicians are professionals who make decisions based on their education and training, not just based on their financial self-interest.

I don’t want to suggest that reimbursement has no effect on physician practice. There is compelling evidence that some medical students choose a particular specialty because, overall, it is far better paid than another one. The Medscape Physician Compensation Report for 2016 reveals the large and persistent gap between the earnings of different specialists: orthopedists make $443,000 whereas general internists make only $222,000, with general surgeons in between at $322,000. Geriatricians, incidentally, with the complete absence of procedures, earn less than anyone else. I agree that reimbursement schemes have the potential to influence behavior to some extent, perhaps more so for hospitals than for individual physicians (or even group practices).

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What I mainly want to suggest is that tweaking reimbursement, by itself, is not likely to be enough to dramatically change practice. If we want physicians to change the way they care for patients, we need to modify what they learn in medical school and residency. We need to educate patients to expect something different from what they expect today. And we need to limit the capacity of drug companies and device manufacturers to sway opinion with huge expenditures on marketing.

Everyone wants "value." It's a great word: after all, who wouldn't want something that is valuable? But I'm not persuaded that it is wise for CMS to plan to convert all reimbursement to VBP over the next few years, as it is planning. If we don't make other far more profound changes, modifications of education, training, and cultural expectations, the revisions of the reimbursement system are destined to fail.

American medicine is best at taking care of people who have a single, very serious disease. We’re even better at taking care of them when they are in the throes of an exacerbation of that disease, when we can control everything that goes into their bodies and monitor whatever comes out, usually in the acute care hospital, often in the ICU. That means, for example, patients with severe heart failure who develop acute pulmonary edema, or people with leukemia who are in “blast crisis.” People who have multiple interacting conditions or one disease that isn’t necessarily fulminant but affects many aspects of their daily lives—those are the people we’re not so good at taking care of. And it turns out that these ill-defined groups of people not only get mediocre medical care, but they also cost the health care system a great deal of money.

It’s finally become clear to a number of influential health policy types that this group deserves attention—doing a better job caring for them could potentially improve health and save money. David Blumenthal, president of the Commonwealth Fund, recently published an article in the New England Journal of Medicine saying it was time we paid attention to “high need, high cost” patients. CTAC, the Coalition to Transform Advanced Care, just held a national forum on “advanced illness care,” advocating payment and delivery reform of the most vulnerable patients. CAPC, the Center for Advancing Palliative Care, has for a number of years promoted the use of “an added layer of support” for patients with “serious illness” throughout the course of their disease. But how can we identify just who it is who stands to benefit from the kind of care that all these groups recognize as crucial: integrated, coordinated, team-based, and patient-centered care?

Our neighbors to the north have long recognized the importance of frailty as a concept that gets at what’s common to people with multiple co-morbidities, patients with one advanced illness, and some patients who have dementia or mental illness. What’s unique about frailty is that it identifies patients who are vulnerable to external stresses. It doesn’t matter whether the vulnerability arises from the interaction between several different medical conditions or the effects of a single disease on many bodily functions; it’s the precariousness of their condition that makes frail people both difficult and costly to care for. 

Dr. Kenneth Rockwood, together with colleagues at Dalhousie University in Canada, has developed a powerful Clinical Frailty Scale that categorizes patients based on a mixture of disease burden and function. Studies show the Clinical Frailty Scale can predict decline and mortality among community dwelling older individuals; it can predict unplanned hospitalization and death in outpatients with cirrhosis; and it can predict length of stay in older patients admitted to the acute medical service of a general hospital. But a Google search fails to turn up a single article in which the CFS is used in a US hospital. It’s been tried in Australia. It’s used in Canada. But not the US. Why not?

Let’s have a look at the CFS. I think it offers some clues:

Two observations about the scale. First, although the outcome is quantitative (every patient gets a score between 1 and 9), the assessment that goes into determining the outcome is fundamentally qualitative. Second, and not unrelated, there’s no way the score can be computed from information already entered into an electronic medical record. That’s because the rating is not based on things like the serum albumin or the mini-mental score. It’s based on one person, a clinician, deciding which of 9 very short, illustrated descriptions best fits another person. There’s nothing complicated about the process—a good primary care physician be sufficiently knowledgeable about his patient to determine the answer without asking doing any kind of special evaluation, and even a not-so-good primary care physician should be able to find out enough to choose the best description after 1 or 2 minutes of questioning. But introducing the CFS into the practice of medicine in the US would require physicians to be aware of their patients’ level of functioning in everyday life, not just the functioning of their individual organs. And it would require accepting the notion that sometimes qualitative reasoning trumps the quantitative. Both concepts are alien to standard American medicine.

CTAC and CAPC and all those others who argue that we need to do a better job caring for our most medically vulnerable patients—for the sake of their well-being and for the sake of our pocketbook—argue about what exactly is wrong with the patients they want to serve. Are they dying? Do they have lots of problems? Are they suffering from advanced illness? I would argue it's not just people who are dying, though many of the most vulnerable are dying. It’s not just people with multi-morbidity, though many of the vulnerable do in fact have multiple conditions. And it’s not just those with advanced illness, though many of the most vulnerable have an advanced illness. It’s people whose illness(es) affect sufficiently many aspects of their daily functioning that they have become frail. 

Frailty is the final common pathway, whether you're frail because of dementia or metastatic cancer or Parkinson's disease or some combination of arthritis, diabetes, and COPD. So let’s borrow from our northern neighborhood and begin using the Clinical Frailty Scale. It’s really very simple.