November 15, 2011

What's $3 Billion Anyway?

GlaxoSmithKline (GSK), the fifth largest drug company in the world, just settled with the Department of Justice for a cool $3 billion. It implicitly acknowledged guilt for a multitude of sins, principally but by no means exclusively for doing everything within its not inconsiderable power to sell its diabetes drug, Avandia (rosiglitazone, still on the market but available only through a “restricted access program”), despite clear evidence that the drug posed significant cardiovascular risks. GSK tried to suppress doctors who raised concerns about Avandia. It funded biased “medical education” programs to “teach” physicians about the merits of Avandia. It manipulated research findings to portray the drug in a positive light.

The GSK deal tops the previous record, the $2.3 billion settlement made by the number one drug manufacturer, Pfizer, in 2009 for illegally promoting its pain-killer, Bextra (valdecoxib, now withdrawn from the market), for non-FDA-approved indications. But the day the settlement was announced, GSK’s stock price remained unchanged. Clearly, the company had already budgeted for its anticipated “fine.” If anything, investors breathed a sigh of relief—the legal case was history and, all things considered, the outcome wasn’t as bad as it might have been.

The charges against GSK are virtually identical to those in the earlier Justice Department case against Pfizer. And they’re very similar to the case against Merck for its handling of the anti-inflammatory drug Vioxx (rofecoxib, now withdrawn from the market), as well as to the $1.4 billion case against Eli Lilly for illegal marketing of the antipsychotic drug Zyprexa (olanzapine) and the $1.3 billion case against Abbott Labs for unacceptable promotion of the anti-seizure drug Depakote (valproic acid). GSK was found to have promoted the drugs Paxil (paroxetine) and Wellbutrin (bupropion) for off-label indications: while physicians are allowed to prescribe a drug for any plausible indication once it has been approved, pharmaceutical companies are prohibited from marketing drugs for non-FDA-approved conditions.

The pattern of abuse found at GSK is evidently endemic and persistent—it has endured in many of the major drug companies over a period of years. What does this say about the regulations that are supposed to protect consumers? At the same time that some politicians are advocating rolling back regulations, claiming they stymy progress, critics of the drug industry argue that the federal government needs to devote more resources, not fewer, to enforcing existing regulations. Other critics, such as Kevin Dufferson of the BU Health Law Program, suggest that the current regulations are inadequate deterrents. He describes the $3 billion payment as merely “a speed bump,” saying the company will merely regard it as “the cost of doing business.” Compared to GSK’s 2010 revenues of $36.2 billion, the settlement with the Department of Justice is arguably small potatoes. Drug companies know exactly how much the DOJ and the FDA devote to investigating and prosecuting drug fraud cases; their cost-benefit analysis persuades them to continue to violate the regulations with impunity. Only when their CEO’s are prosecuted and sent to jail, some critics claim, will the situation change.

On balance, regulation seems essential to protect the health and safety of the consumer. Without regulations, drug companies would likely distort and mislead in promoting all their drugs, not merely the blockbuster drugs where they have the most to gain. Better enforcement and greater executive accountability may well improve drug company behavior. But given that the policing alone is unlikely to guarantee integrity, it is also essential that drug companies fundamentally alter their organizational culture. Only with deep-seated cultural change will deliberate falsification of data become unthinkable. Only when a new ethos prevails will it become impossible to mistake propaganda for science. The CEO of GSK claims that just such a process is underway: a press release asserts that the company has hired more “compliance staff” and it has strengthened its training programs on ethical conduct. Most importantly, it has changed its incentive compensation program for sales reps so as to reward them based on customer evaluation and selling “competency” rather than on meeting sales targets. Whether a profit-driven company can truly reform its culture without changing its fundamental mission remains to be seen.

October 07, 2011

Is the Hospital Bad for Your Health?

Decreasing the risk of readmission to a hospital is a hot area of research. It has been a target for quality improvement ever since a study in the New England Journal of Medicine found that just under 20% of all fee-for-service Medicare patients who had been hospitalized during 2003-2004 were readmitted within 30 days of discharge (. The estimated cost of all the unplanned readmissions (90% were assumed to be unanticipated) was a cool $17.4 billion.

The NEJM study was widely interpreted to imply that these patients received sub-optimal care, quite possibly downright poor care. Either they were discharged before their condition was adequately diagnosed or treated, or the plan for follow-up care was inadequate. Sometimes patients were admitted for one problem, say heart failure, but were found to have a second problem, say anemia, and the primary problem was addressed but the second one was not. Sometimes patients were sent home on the wrong medicines—an important medication had been accidentally omitted during the hospital stay and wasn’t restarted when the patient returned home, or a medication was “held” during the hospitalization for good reasons but should have been resumed on discharge at a lower dose. Or patients were simply overwhelmed when they went home and confused about exactly what pills they were supposed to take and what appointments they were expected to make. In response to the high readmission rates, countless programs and projects have been developed to decrease “avoidable” readmissions, which are both burdensome to patients and costly to society. Some of these programs have reported dramatic successes; most have moved the dial only a little bit.

Now two new reports in the medical literature shift the focus from “readmissions” to all hospitalizations near the end of life. For many patients, hospitalization entails risk (for instance, hospital acquired infection, acute confusion associated with a changed environment). As people approach the end of life, these risks may outweigh any benefit. The benefit/burden balance shifts even more decisively for nursing home residents with advanced dementia, to whom invasive medical interventions are incomprehensible, frightening and, given that they are close to death, at best minimally useful. One of the new studies looks at exactly this group of patients, individuals they for some mysterious reason refer to as having “cognitive issues” when in fact they have severe, endstage dementia. What the investigators found was that 19% of such individuals experienced at least one “burdensome transition” in the last 90 days of life.

The definition of “burdensome transition” is a bit complicated: it includes any kind of transition to a new form of care in the last 3 days of life, or multiple hospitalizations in the last 90 days of life, or lack of continuity in nursing home care in the final 90 days. I could quibble with some of these measures. For example, hospice enrollment in the last 3 days of life (occurring in 4.4% of the nearly 475,000 nursing home residents who died between 2000 and 2007) is less than ideal, but for dying patients surely it’s better than not enrolling in hospice at all. The degree of burden is very different for these patients, say, than for the 4.2% of patients who were hospitalized 3 or more times in the last 90 days of life. But the main point of the article remains valid: some nursing home residents who are close to the end of life are subjected to interventions that are painful (to them) and costly (to society) for little if any benefit to anyone.

The second study asks how many Medicare fee-for-service patients had an inpatient surgical procedure in the year before their death. What they found is that among the 1.8 million Medicare beneficiaries who died in 2008, 32% had an operation in the hospital during their last year of life. In fact, 18% had a procedure in the last month and 8% in the last week of life. Now, it’s important to remember that, as with the previous study, neither the physicians nor the patients could have known with certainty that death would come very soon. Most likely, surgeons offered the procedure in the hope, however slim, that it would improve quality of life (for example by repairing a fractured hip) or prolong life (by opening a narrowed coronary artery). And in fact, surgery may well have been life-prolonging in all those patients who underwent an operation but by definition didn’t make it into the study because they didn’t die. Nonetheless, the study points to the indisputable reality that a large number of older people had surgery, especially individuals in their seventies, only to die within a year.

The message most readers will take away from these studies is that American medicine continues to over-treat patients, fueled by the technological imperative and by our refusal to come to terms with our own mortality, and paid for by Medicare’s generosity. That’s an important message, though one we’ve heard before. But I think there’s a second message as well. If we want patients or their surrogates to consider forgoing hospitalization, patients who are very old and ill and in some cases severely demented, we need to offer them a reasonable alternative. Nursing home patients ought to already have such an alternative available to them: most were hospitalized for infections or dehydration, both of which should in principle be treatable in the nursing home. But evidently 19% of the time (and considerably more often, in some states), we don’t provide patients, even in the nursing home, timely assessment of an acute medical condition. We don’t send a physician or nurse practitioner to evaluate their fever or their lethargy (possible signs of infection and dehydration, respectively). We don’t offer simple blood tests and basic X-rays in the facility. We don’t routinely administer intravenous antibiotics or fluids. We don’t provide vigorous symptomatic treatment of shortness of breath and agitation, which commonly result from infection. Instead, we give patients the alternatives of hospital treatment or no treatment. “No treatment” is not an acceptable option.

Likewise for the case of surgery. If we want patients to contemplate forgoing surgery, we need to offer a viable alternative. We need to explain that medical therapy for a gallbladder infection has a good chance of treating the problem, that surgery to prevent recurrence makes sense for someone with a 10- or 20-year life expectancy, but not for someone with a 1- or 2-year life expectancy. We need to explain that medical treatment for coronary artery disease may well be successful and that placement of a stent or, even more invasive, coronary artery bypass surgery, may be excessively burdensome.

As physicians struggle to develop a better way to care for their elderly patients, they will need to develop creative strategies to keep patients out of the hospital and to prevent those who are admitted from recidivism. To achieve this end, physicians will need to design models of care that offer a robust alternative to the hospital. The troubling truth behind the reports in the NEJM and the Lancet is that much of American primary care offers no acceptable treatment for acute medical problems other than hospitalization. Only hospice provides care that is in time, comprehensive, and compassionate. For those patients who meet the criteria for hospice enrollment and who accept an approach focused exclusively on comfort, hospice is a wonderful program. For the many frail, sick, older individuals who are in the final phase of life but who are either not hospice eligible or who are not ready to forgo all potentially life-prolonging treatment, we need another approach. We have to provide better care in the home and the nursing home—with both qualified clinicians and the many low tech diagnostic and treatment interventions that can make a difference to patients—if we want to give high quality care outside the hospital.

September 26, 2011

Is the Fountain of Youth Spouting Contaminated Water?

A few days ago, the prestigious biomedical journal Nature reported that the water in the Fountain of Youth was contaminated. While the article’s title didn’t exactly have the ring of a call to battle, “Absence of effects of Sir2 overexpression on lifespan in C elegans and drosophila,” (AKA roundworms and fruit flies) it raised the hackles of pro-longevity scientists. What’s the fuss about and what are the prospects for improving the health of older people through gene manipulation?

Back in the early 1990s, Leonard Guarente of MIT began doing innovative research on genes coding for a protein called Sir2 in species such as roundworms and yeast. The analog of these proteins in mammals is a family of 7 proteins, SIRT1 through SIRT7, collectively known as “sirtuins.” One of Guarante’s early findings was that stimulating production of SIRT1 induced changes in mammals comparable to the life-prolonging effects of calorie restriction. But while decreasing food intake to starvation levels may lengthen life in rats and mice, it hasn’t yet been shown to have the same effects in primates and, more importantly, its prospects as a panacea against aging seem dim in an era when obesity is epidemic. The sirtuins turned out to have a variety of anti-inflammatory and anti-metabolic effects, reportedly protecting against cancer, diabetes, heart disease, and dementia. While it’s wise to be suspicious of any substance that claims to produce such a wide array of benefits, conjuring up the patent medicines of the nineteenth century, Guarante has soberly spelled out many of the discoveries about the sirtuins, writing in a recent review in the New England Journal of Medicine (June, 2011).

Seeking to translate his research findings into drugs that might prevent many of the diseases of old age, Guarente founded Elixir Pharmaceuticals in 1999, partnering with other researchers in the aging field, including centenarian specialist, Tom Perls of Boston Medical Center. Elixir has raised roughly $43 million in venture capital and has 9 drugs in various stages of testing, but as yet no FDA-approved product.

One of Guarante’s postdocs, David Sinclair, made a splash in 2003 when he discovered that resveratrol, a chemical in red wine, could mimic the life-prolonging effects of calorie restriction. Building on this work, he founded a second pro-longevity company in 2004 together with entrepreneur Christoph Westphal, a company that he called Sirtris. According to its website, Sirtris has 7 drugs in the pipeline, all in the earliest stages of testing. The company was purchased by GlaxoSmithKline in 2008 for $720 million. Since that time, Sinclair has become a full professor at Harvard; Westphal resigned as CEO after he was noted to have developed a nonprofit venture called the Health Lifespan Institute, which was selling a year’s worth of resveratrol to customers for $540. In late 2010, GSK halted a trial of resveratrol, a naturally available (read: unpatentable) substance and is focusing exclusively on the synthesis of small molecules that activate sirtuin proteins.

The new article in Nature challenges some of the early studies purporting to demonstrate that Sirtuins mediated the effects of calorie restriction in mammals. It does not undercut the now extensive body of work demonstrating the multiple roles of sirtuins. It does not diminish the appeal of the sirtuin approach, which targets the biochemical process underlying the development of degenerative diseases such as cancer, diabetes, heart disease, and dementia in the first place.

What remains to be seen is whether any of the elaborate studies in molecular biology will in fact produce drugs that prevent disease in people—without adversely affecting other important cellular processes. It’s worth a try. It’s also a good test case for whether collaboration between university-based, NIH and philanthropically funded science (Guarente at the Glenn Laboratory for the Science of Aging at MIT and Sinclair at the Paul Glenn Laboratory for the Molecular Biology of Aging at Harvard) Medical School, and profit-driven drug companies (Elixir Pharmaceuticals and Sirtris of GlaxoSmithKline, both in Cambridge, Massachusetts) will help aging Americans.

June 30, 2011

The Way Forward

The rising cost of the Medicare program has suddenly gone from the concern of a handful of Cassandras like the distinguished biomedical ethicist Daniel Callahan and the former Congressional Budget Director Peter Orszag to a central preoccupation of the US Congress. Gutting Medicare, as the Republican Congressional leadership has proposed, has proved decidedly unpopular: Americans like their government-run health insurance. So how will we put the brakes on Medicare spending? Surprisingly, we may have something to learn from Massachusetts?surprising because health care reform and health care cost containment efforts in Massachusetts focus exclusively on the private sector.
Massachusetts rolled out universal health care coverage in 2006 and began trying to address costs two years later. This month, the Attorney General's Office issued a report analyzing trends in cost control so far. The bottom line is that costs are still spiraling upwards but perhaps more importantly, we have a sense of what strategies might work and which will not.
Before embarking on cost control, Massachusetts commissioned a study to lay out the leading potential cost containment options. Using sophisticated analytical models, the researchers estimated which strategies had the greatest chance of working and just how much of an effect each was likely to have. State government then advocated utilizing selected options from each category, but extended varying (some would say very limited) direct financial support for each of those identified as promising. The Governor publically endorsed bundling payments, an approach that research indicated would have by far the largest effect on reining in costs.
Fundamentally, cost savings arise from either lower prices or a lower volume of services (or both). Possible strategies can be lumped into 4 principal categories: reforms of the payment system, redesign of the health care delivery system, reduction of waste, and promotion of consumer engagement. What has worked, what didn't and what are the obstacles to success?
In the category of reforming the payment system, the technique strongly encouraged by Massachusetts was bundling payments. The most widely touted version is the Accountable Care Organization (ACO), in which provider groups, hospitals, skilled nursing facilities, and other health care groups band together to provide all the types of care a patient might need. The insurance company pays the ACO a single capitated payment for each patient who receives care through the organization. The members of the ACO are forced to "manage" the care and to share the risk. One example of this approach is the "Alternative Quality Contract," in which Blue Cross/Blue Shield offered participating physician practices a global payment for each enrolled patient. The innovative features of this model included providing extra payments for achieving quality and insurance against the high costs from outliers. BC/BS claimed that the project was a resounding success. The Massachusetts Attorney General's Office is not convinced, arguing that while the goal was to decrease the rate of rise of costs, and there was indeed evidence this occurred, total costs went up and not only that, but they did so to a greater extent among physician groups participating in the program than among those that did not. The moral, the Massachusetts report concluded, is that bundled payment strategies might work, but the overall payment has to be small enough to give physicians an incentive to decrease utilization or refer patients to low cost hospitals.
In the realm of redesign strategies, Massachusetts endorsed the "medical home." This is a new name for an old idea: ensuring that all patients have a primary care physician and expecting that physician (perhaps together with a larger team of clinicians) to coordinate care. The problems, as the report reveals, are that certain organizational structures such as a Physician Provider Organization (PPO) do not require that patients have a primary care physician. Coordination of care in such a non-system (there is no structure linking those clinicians who are ostensibly part of a PPO) is impossible. Another difficulty is the shortage of PCP's in the state; even if patients had a financial incentive to designate a PCP, say a premium reduction, there are simply not enough primary care doctors to go around.
In the area of value-based decision-making, the state is attracted to tiered or restricted network health insurance plans. The idea is to make patients "have skin in the game" by structuring their co-payments, say for physician services, according to whether they select an "efficient" clinician or an "inefficient" clinician. The expectation is that market forces would drive patients towards use of physicians who have shown they can achieve good outcomes at a low cost. Similarly, restricted network plans limit the patient's choice of hospitals or physicians to those that are "efficient." The health plan determines who is efficient and who is not using very blunt indicators: no outcome measures are used for evaluating physicians and a handful of standardized "quality indicators" are used to measure hospital performance. Only a few companies have developed such insurance products, but they may be catching on.
The final arena is reduction of waste. The most interesting idea in this category, using cost effectiveness analysis to decide what tests and treatments insurance companies will cover, was dismissed out of hand in the preliminary report commissioned by the state because of a paucity of empirical studies or other data to inform the analysis. Given that none of the other strategies is proving dramatically effective, perhaps it's time to examine this idea more closely.
The assumption underlying a focus on cost effectiveness analysis is that the high cost of medical care is driven to a large extent by technology, a claim supported by numerous studies. Technology, whether a screening test such as cardiac computed angiography, a monitoring test such as a positron emission tomography (PET) scan, or a treatment such as targeted cancer chemotherapy, sometimes improves patient outcomes and sometimes does not. Once a technology has been approved for use (whether based on the FDA's "safe and effective" criteria or Medicare's "reasonable and necessary" criteria), physicians often use it with impunity, typically in a variety of situations for which it was never approved. It's time to recognize that placing the responsibility for cost control on physicians is problematic as long as the culture of medicine (often buoyed by the incentive structure) promotes widespread use of the latest and ostensibly greatest tests and procedures. Placing the onus of cost control on patients is problematic because patients rely on the professional expertise of their physicians to recommend tests and procedures. Moreover, the very nature of health insurance defines the true consumer as the physician, not the patient. Health plans will need to start making more rational decisions about what they will cover. They can choose to pay for the least expensive, proven treatment and patients can opt to pay the difference between the cost of the covered treatment and the unproven therapy their physician recommends. Only when we start rationalizing physician prescribing can we expect to make progress in constraining medical costs. And rationalizing physician behavior will require payment reform, delivery system design, and health plan coverage decisions.

April 22, 2011

New Cancer Treatments: Hype or Hope?

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.

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.

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.

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.