Kicking the Bucket

Even though you think and behave perfectly normally, you might already have Alzheimer’s disease. In fact, you might warrant the label of  “pre-clinical Alzheimer’s disease” for a full 20 years before graduating to the full-fledged condition. That according to the latest definition of Alzheimer’s put forward by the National Institute on Aging together with Alzheimer’s Association 3 years ago.

Heralded as a radical departure from earlier clinical diagnostic criteria, the new definition is in line with how we think about other chronic conditions such as cancer or heart disease. Normal cells often mutate into cancerous cells and proliferate for a long time before there are enough of the to produce symptoms—and a cancer diagnosis. Plaques may be deposited in the lining of coronary arteries long before they narrow blood vessels enough to impair blood flow to the heart resulting in chest pain. In all these cases, the hope is that we may be able to intervene during the pre-symptomatic phase, altering what is currently the inevitable trajectory of illness. In the case of Alzheimer’s, detecting various “biomarkers” in the blood or cerebrospinal fluid would signal the need for some kind of biochemical intervention. The problem has been that we don’t as yet have any such intervention. For now, the main purpose of early diagnosis is to identify people who could enroll in research on the prevention of Alzheimer’s—assuming the diagnostic techniques are sufficiently reliable and the benefits of research outweigh the burdens of knowing what the future has in store.

Philosopher Dena Davis makes a different case for the value of early diagnosis in this month’s Journal of Medical Ethics. Knowing that a person is destined to develop dementia, she argues, is invaluable so he can kill himself.

The option of “rational suicide,” as Davis calls it, is based on wanting to avoid becoming dependent and on wanting to spare family the burden of caregiving, as well as the potential loss of an inheritance. The diabolical nature of dementia is that if you wait until you are a burden, until you can no longer do any of the things that once gave meaning to your life, then you will most likely have reached a stage where you have also lost the ability to take your own life or even to remember that you ever wanted to end your life if you developed advanced dementia. And those countries (such as Switzerland, Belgium,  and the Netherlands) and those American states (Montana, Oregon, Washington, and Vermont) where Physician Assisted Suicide (PAS) is legal all require that the patient be of sound mind at the time the request is made and that she have a prognosis of not more than 6 months. So PAS is not generally an option for people with dementia.

There is a gentler alternative to pre-emptive suicide, and that is drawing up an advance directive that authorizes the withholding of life-prolonging medical treatment in the event of dementia. But Davis discounts this option, claiming that courts and ethicists increasingly dispute the right of a person, while cognitively intact, to make any claims about the interests of his future demented self.

In fact, opponents of pre-emptive suicide such as Rebecca Dresser, whose response to Davis appears in the same issue of the ethics journal, say something a little different. They do not assert, as Davis contends, that competent Jane Doe should have no say over what happens to incompetent Jane Doe. That would make little sense as much of the point of advance directives is to plan for possible loss of competence. Rather, Dresser argues that “precedent autonomy,” in particular the choices made when competent, should be tempered by considering the present interests of demented Jane Doe. This is the dilemma of the happy dement that Dresser addressed in an earlier article on the subject. 

Suppose that today I am an anxious, driven, competitive person. I find the prospect of being unable to write articles or give talks or care for patients intolerable. But suppose that one day, I do lose my ability to write articles and give talks and care for patients. And suppose that lo and behold, I am no longer anxious or competitive. Instead, I am relaxed and cheerful. I smile at everyone indiscriminately. I am no longer inhibited and I clap my hands and tap my feet to all kinds of music. I’m no longer a picky eater and instead I say everything I’m served, no matter how bland or poorly prepared, is delicious. I don’t recognize my children but am glad to see them, just as I’m glad to see the aide who dresses me in the morning. Surely my best interest is in continuing to live as long as I can remain in my current state.

The challenge, as I think Rebecca Dresser understands and Dena Davis does not, is to balance the perspectives of Jane-Doe-ten-years-ago and Jane-Doe-today. How should we do this and who should be the arbiter? The way to proceed, I believe, is for former Jane Doe to identify the goal of care for her future self. Plausible goals are the prolongation of life, maximization of quality of life, or promotion of comfort. Death, parenthetically, is not a goal; it is a means to an end. Only rarely is it the only or the best means to achieving a legitimate goal. Most people, I suspect, would choose comfort as the goal in advanced dementia and maximizing quality of life as the goal in moderate dementia. All the physician needs to do is to translate that goal into practice. For an acute medical problem such as pneumonia, for example, comfort means using Tylenol to keep fever at bay and oxygen to ameliorate shortness of breath. Maximizing quality of life may mean using oral antibiotics—but not hospitalization in an intensive care unit with a ventilator for breathing.

We will never entirely be able to prevent people from committing suicide upon learning they are at substantial risk, if they live long enough, of developing clinical Alzheimer’s. After all, people can kill themselves when diagnosed with a disease such as metastatic cancer, even before they develop intolerable symptoms, though few do so. They could kill themselves prophylactically at age 65 or 70 to assure they will never get any awful disease, though most people do not choose this route.  Our responsibility, however, as clinicians, ethicists, and lawyers is to try to make sure that every individual can live as good a life as possible, whatever cards she has been dealt. That’s what a good society does.

Big Data, Small Data, Any Data At All

Why is it that I still remember that the formula for the volume of a sphere is 4/3π r³, which I learned in tenth grade geometry? And why is it that I never even heard of a p-value, the measure commonly used to assess whether a result is “statistically significant,” until I was in medical school? I haven’t had any occasion to compute the volume of a sphere since I took calculus in college, but I have to interpret statistical findings all the time. Something is not right here.

Understanding at least the rudiments of statistics matters—and not just to me, a physician who has to make decisions about how to treat patients by evaluating articles in the medical literature that rely on statistical methodology. Understanding basic statistics matters to everyone. You need to know some statistics to realize that it is more accurate to measure the population by using sampling techniques than by trying to count everyone. You need to know some statistics to understand why Nate Silver, with his FiveThirtyEight website, was so much more on target in his predictions about the 2012 presidential elections than anyone else. And you need to know some statistics to decide, as a patient, how to evaluate the options your physician presents you with.

Just this morning, I read an article in the first section of the NY Times “Study Discounts Testosterone-Suppressing Therapy for Early Prostate Cancer.” It turns out that millions of men with early stage prostate cancer, mainly men over the age of 65, have been treated with “Androgen Deprivation Therapy” (ADT), either by bilateral orchiectomy (surgical removal of the testes) or by drugs. A new study, published in JAMA Internal Medicine, concludes that ADT in such men does not prolong life. It does cause lots of side effects, ranging from osteoporosis to weight gain, to decreased libido, to diabetes. The article quotes one expert who was not involved in the study as saying that the findings were “eye-opening and even alarming.” According to editorial writers from the Dana Farber Cancer Institute, the treatment is a good candidate for inclusion in the “Choosing Wisely” campaign, a national effort to eliminate the use of “low value medicine;” that is, treatments that achieve little, given their cost. The article fits in nicely with a major theme of JAMA Internal Medicine, which has a section called “Less is More.” It’s a theme that resonates with me as well: I often argue on this blog that certain treatments, especially when provided to frail, older individuals, may cause more harm than good. Finding that a commonly used treatment, such as ADT in older men, doesn’t do what it promises, would not be at all surprising to me. But is it true?

I looked up the article, which isn’t actually in the print issue of the journal yet; it was published in the “online first” section, which gets important articles distributed quickly. The authors looked at data on 66,717 men age 66 or older with localized prostate cancer diagnosed between 1992 and 2009. They defined “primary ADT” as orchiectomy or the use of a drug such as a luteinizing hormone releasing agonist (a drug that stimulates the pituitary to signal the testes to make testosterone until they run out, at which point testosterone levels fall) as the sole cancer therapy given to men with localized prostate cancer within 6 months of diagnosis. The outcomes they were interested in were cancer specific mortality (that is, the death rate from prostate cancer) and overall mortality. So far so good. 

But since this was not a randomized study in which some men got ADT and others received conservative management (ie no treatment unless symptoms develop), with the selection made based on the flip of a coin, there was no reason to believe that the two groups of men would be similar to one another. In fact, they were quite different. The men who got ADT were a good bit older than those who did not (average age 79 vs 77). They were considerably sicker, with higher rates of other diseases such as heart disease or lung disease. And they were far more likely to have “high risk” prostate cancer, based on the characteristics of the cells in their tumors (47.7% vs 23%). Their PSA scores were also much higher (an average of 19.5 in the ADT group compared to 11.1 in the other men, where 4 is the typical cutoff for normal). Simply comparing the outcomes in these 2 very dissimilar groups of men would not tell the whole story. Somehow, the authors needed to try to compensate for the inherent differences between the men. The only way to do that (other than scrapping this approach entirely and randomizing men to get ADT or some other treatment), is to build a statistical model.

Build a model the study authors did. The specifics of what they actually did are too complicated to describe here. I’m not sure I fully understand what they did, but it involved a technique called “Instrumental Variable Analysis,” known as IV. Suffice it to say that when they used this approach to try to adjust for all the differences between the groups (only some of which they could specify), they concluded that the 15-year prostate cancer specific survival rate was 85.4% in both groups. And when they used a different method, the Cox multivariate model, they found the mortality rate was 2.4/100 in the ADT group and 1.1/100 in the group treated with conservative management or, after attempting to adjust for differences based on what was known about other illnesses, PSA levels, etcetera, the group treated with ADT was 1.53 times more likely to die.

What the reader needs to understand is that the results of the study depend entirely on which model you choose. If you select IV, and the authors try hard to make the case that this is an excellent choice, but which some experts think is a flawed approach, you find that ADT and conservative therapy are equivalent. If you select the more conventional approach, you find that ADT is actually worse than watchful weighting. Since neither model predicts that ADT is better than conservative management, perhaps it follows that ADT is just a bad choice for the treatment of early prostate cancer in older men. The right conclusion, I think, is that we don’t actually know what to make of ADT. If we chose yet another model, perhaps we would find that ADT is superior.

Learning about different study designs—which ones you can trust, which ones are merely suggestive and which have to be confirmed using a better, more reliable approach—is what kids should be learning in high school and college. Learning about probability and statistics is what kids should be learning, not trigonometry and solid geometry. Our math curriculum reflects seventeenth century mathematical knowledge (it typically includes elementary algebra, Euclidean geometry, and perhaps calculus, created in the fourth century BCE and the seventeenth centuries respectively). 

Today, big data is all the rage and there is a growing enthusiasm for learning how to milk large data sets for useful information. But the reality is that it’s not just big data that’s important and it’s not just important for a small cadre of people. We all need to learn how to make sense of what we read in the newspapers, of what our doctors tell us about different treatments. And to do that, we need to develop basic statistical literacy.

Remembering Tacrine

A shiver went down my spine when I looked through the New England Journal of Medicine on November 13, 1986. There, in typically stodgy medicalese, was the report of a study that claimed to dramatically improve the cognition of patients with moderate to severe Alzheimer’s disease. It was what I, as a recently minted geriatrician, had been fervently wishing for but despaired of ever seeing—a glimmer of hope that we would have a medication to treat patients with Alzheimer’s disease. So I was struck in reading this week’s “Feature” article in the BMJ, “Alzheimer’s disease: still a perplexing problem,” by the author’s observation that the few drugs available for treating Alzheimer’s today are all agents that, like the drug I read about in 1986, target the production of the neurotransmitter, acetylcholine, which is vastly decreased in the brains of people with Alzheimer’s. In fact, most of the existing drugs are “anticholinesterases,” derivatives of the drug reported on in 1986, tetrahydroaminoacridine (ultimately shortened to tacrine). The only available drug for Alzheimer’s that isn’t an anticholinesterase is mementine (Namenda) approved by the FDA in 2003, which also affects acetylcholine but works in a different way. None of these drugs is terribly effective and NICE, the British agency that advises the National Health Service on coverage for drugs and devices, gives them only the most tepid recommendation.  So what, I wondered, ever happened to William Summers, the lead author of the original New England Journal study that created such a stir nearly 28 years ago?

I was familiar with the early history of William Summers and tacrine (THA). The New England Journal of Medicine published an editorial along with the article, heralding the drug as a breakthrough, but the community of Alzheimer’s researchers reacted with venom. They commented on the shortcomings of the study: it only involved 17 patients, the patients served as their own controls, and the conclusions rested on the patients’ performance on a handful of tests of cognition, some of which were unfamiliar or of questionable clinical importance, including a “global assessment of cognition” performed by the examining physician. All valid concerns. Nonetheless, the findings were impressive: the difference between treated patients and untreated patients was statistically significant with a p-value of .0003. That is, if THA actually were ineffective, the chance of the investigators observing what they did was about 3 in 10,000. And the authors didn’t claim to have discovered a miracle drug. They said: “These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer’s Disease. We stress that further observations will be required before a clearer assessment of the role of this agent can be made.”

The deeper concern seemed to have nothing to do with the merits—or weaknesses—of the study. Basically, the question was: Who is William Summers? Summers was not part of the established Alzheimer’s research community. He carried out the study on patients in his private practice. He had gone to medical school and completed a residency in Internal medicine and Psychiatry at Washington University in St. Louis, Missouri and had been on the faculty at the University of Pittsburgh, the University of Southern California and, at the time the initial article came out, at UCLA. But he had no funding, let alone facilities or other forms of support, from either a major research university or a drug company. He had little background carrying out research. In short, he wasn’t one of the boys.

The National Institute on Aging and the Alzheimer’s Association agreed to jointly sponsor the Tacrine Collaborative Study Group to evaluate the drug more definitively. But in the course of its review of Summers’ research, a routine step that takes place when a researcher applies for a chemical to be considered as an “investigational drug,” the FDA uncovered a variety of sloppy research methods. For the next 3 ½ years, Summers and the FDA were at war until finally, in 1991, the FDA formally exonerated Summers of all substantive charges. UCLA, the medical school where Summers had an appointment as a Research Associate Professor, also conducted an investigation. Reporting for the LA Times, writer Janny Scott quoted the panel as finding “severe shortcomings in the design, execution, and report of Summers’ study” but concluding that “these limitations did not undermine the conclusion that the drug had helped some of the patients studied.”

The Tacrine Collaborative largely confirmed Summers’ early findings, this time studying 215 patients at multiple different clinical centers. In 1993, the FDA approved tacrine for use in the treatment of Alzheimer’s disease. Tacrine is no longer on the market, but not because it was found to be ineffective. It was simply superseded by another anticholinesterase that is easier to take (dosing is once a day instead of 3 times a day) and that has even fewer side effects than tacrine. The new drug, Aricept, was a blockbuster drug, accounting for $3 billion in sales worldwide in 2010, before it went off patent. Aricept is not a great drug, any more than Tacrine was, nor are the other 2 anticholinesterases on the market, rivastigmine (Exelon) and galantamine (Razadyne). But Aricept, like Tacrine, fills a void. It gives patients and families something to do, some drug to take; and it may confer a modest benefit, at least for a short time. It’s no worse than a great many other drugs we prescribe for patients, many of them far more toxic and far pricier.

And Summers? He dropped out of sight.

Summers didn’t entirely drop out of sight. PubMed, which keeps tabs on all publications in medical journals, lists 13 articles that Summers has authored since the New England Journal paper in 1986, most in minor journals such as the Journal of Alzheimer’s Disease. His most recent paper, published in 2010, is a study of a “complex antioxidant blend” on cognitive function. His website explains that he offers “care not found in modern healthcare system,” and that he uses an “innovative mix” of traditional medicine, supplements, and homeopathic remedies. Clearly, William Summers is way out on the fringe of respectability. But was he always on the fringe, or was he driven out of mainstream medicine, deterred from pursuing an innovative research career, because he was not an insider?

I don’t know the answer. And I recognize the need to adhere to high standards in the research arena. All too many articles are published of studies that use weak if not downright inadequate methodology. But I can’t help wondering: are funding agencies such as NIH as well as private non-for-profit foundations such as the Robert Wood Johnson Foundation stultifying research by limiting funding to very conventional applicants? I wonder, and I worry.