All Eyes are on Medicare

  

            When the FDA approved Biogen’s new Alzheimer’s drug, aducanumab (brand name Aduhelm) on June 7, the reaction was surprise, dismay and, in some quarters, enthusiasm. But everyone was shocked by the drug company’s audacity in setting the price for the medication at $56,000 per year. As one STAT article put it, the only question about the consequences for Medicare, the insurer for close to 97 percent of Alzheimer’s sufferers, was whether the impact would be big, huge, or catastrophic. 

Pharmaceutical manufacturers figured out some time ago that they could bring out “specialty drugs,” typically targeted against a single relatively rare disease, if they charged ten or even a hundred times more than for an average medication. The list price of crizotinib (brand name Xalkori), for example, used against a relatively uncommon type of lung cancer found in non-smokers, is just under $20,000 for a one-month supply—and patients usually take the drug until they die or develop resistance to it. But aducanumab is intended for all people with Alzheimer’s disease, and according to recent Alzheimer Association estimates, that means 6.2 million people over age 65.

            The high price is especially disturbing because it’s not even clear that the drug works. A number of studies have been carried out with similar drugs, other monoclonal antibodies that, like aducanumab, were designed to mop up abnormal brain amyloid deposits, which are the hallmark of Alzheimer’s disease—but none of those drugs proved helpful in practice. The trials of aducanumab were likewise discontinued because interim analysis showed the drug was ineffective. Then, in a surprise move, the manufacturer nonetheless applied to the FDA for approval after a reanalysis of the data showed some evidence of benefit when the drug is given in high doses. The independent scientific review panel convened by the FDA to evaluate the data was not convinced, however, with 10 out of 11 members rejecting approval and one abstaining—but the FDA nonetheless approved the drug.

            Even if aducanumab does work, “work” means slowing the rate of decline slightly, not stopping or reversing the disease process. And the potential side effects of the drug are considerable: 40 percent of patients experienced brain swelling, in some cases of sufficient magnitude to cause nausea, vomiting, confusion, or visual changes. 

            Patients and their families, who are desperate for an effective drug against this progressive, ultimately fatal disease, are eager to try something with promise, anything. But they are worried about the side effects of aducanamab, about the need for regular MRI scans to monitor for those effects, and about its high cost.

            Most critiques of the new drug—and there are many, the NY Times alone has published eight articles on the subject between June 7, when the FDA announced approval of the drug, and July 9 , and STAT has published at least 16—assume that since it has been approved by the FDA it will necessarily be paid for by health insurers. In the case of aducanumab, that will principally be Medicare. In fact, CMS is not obligated to provide coverage for the drug just because the FDA approved it.

            Medicare, like all other health insurance companies, can decide what tests, procedures, and treatments it will cover. The relevant part of Medicare that will be responsible for paying for aducanamab, if Medicare covers the drug, will be Part B: oral medications fall within the jurisdiction of Medicare Part D plans (prescription drug plans), but medications administered intravenously in a physician’s office, such as aducanumab, fall under Medicare Part B. Most determinations of whether to provide coverage for this kind of treatment are made locally, by the private carriers that process Medicare claims. But the decision about coverage can be made nationally if requested by CMS, by the manufacturer, or by members of the medical profession, in which case the decision becomes binding on all the private carriers. Such “National Coverage Decisions” are reviewed by an internal arm of CMS, the Special Coverage and Analysis Group. For particularly controversial decisions, especially if they have social or ethical implications, CMS may request the guidance of the quasi-independent committee, MEDCAC, the Medical Evidence Development and Coverage Advisory Committee. This is a group of 100 experts including economists, ethicists, physicians, scientists and others, from whom a subgroup of 15 is selected to provide in-depth analysis on the particular test or treatment under consideration. 

            Since its inception, MEDCAC (or its predecessor, the Medicare Coverage Advisory Committee), has issued 348 National Coverage Decisions. These comprehensive analyses have addressed topics as diverse as cardiac pacemakers, Pap smears, and lipid testing. On rare occasions, they have dealt with drugs, for example, an intravenous medicine used in the treatment of heart failure, Nesitiride. When MEDCAC deliberates Medicare coverage for a particular intervention, it can recommend covering the intervention, not covering it, or restricting its use in specific ways. For instance, it advocated coverage of the Left Ventricular Assist Device, an invasive treatment that is almost but not quite an artificial heart, but it required a detailed informed consent process that included a social worker and palliative care expert along with the patient, family, and cardiac surgeon. Ultimately, Medicare approved coverage for the device but set reimbursement at $70,000 (the manufacturer’s price was closer to $200,000) and limited insertion of the device to a handful of medical centers across the country. 

            Medicare is required by federal law to provide coverage for anything that is “reasonable and necessary” for “the diagnosis or treatment of an illness or injury.” Despite years of often contentious debate, there is no precise definition of what this means. The FDA, by contrast, approves drugs and devices if they are “safe and effective.” In the case of aducanumab, it is arguable whether the drug is truly safe and effective, but surely it would be reasonable and necessary for Medicare to restrict the use of aducanumab to early disease (the only group in whom it was tested) and to require an elaborate informed consent process. While Medicare, by established custom, does not reject coverage based on cost-benefit analysis, it could set the price at a level comparable to those of the existing, only marginally beneficial drug treatments for Alzheimer’s disease, drugs such as rivastigmine (brand name Exelon, which has a yearly retail cost, when given as the brand name drug, of $823) and donepezil (brand name Aricept, which has a yearly retail cost, when given as the brand name drug, of $5380).

            Given the controversy swelling around Biogen’s new Alzheimer’s drug, the case for Medicare initiating the National Coverage Decision process is strong. The only reason for failing to do so is external pressure, whether by the manufacturer, by members of Congress under the influence of the pharmaceutical industry, or by the public. If CMS opts against this path or convenes MEDCAC only to reject its advice,* as the FDA did with its advisory committee, that would be a compelling reason to make CMS an independent agency, along the lines of the National Science Foundation, that is under control of a bipartisan board and whose director is independent of the President.

 

            *Between when this essay was drafted on July 9 and edited for publication today, CMS has in fact decided to proceed with a National Coverage Decision.

False Hope

This past week, the House passed its “Right to Try” bill, which would give dying patients easier access to experimental drugs. The Senate has already passed a version of this ill-conceived legislation and Trump is an enthusiastic supporter, viewing it as a means of defanging the FDA and of demonstrating his great compassion for the American people. The bill itself, if it is signed into law, will not affect very many people and most of them are not likely to be elderly. But it is the first step in a campaign to destroy drug regulation. That is an issue for all of us, and for older people, as the greatest per capita consumers of prescription medications, in particular.

A STAT article on the subject quotes Andrew McFadyen, executive director of a non-profit patient advocacy group: “I think this is the first step, for sure. Tear down as many regulations as possible, take away all oversight, and let it be the Wild West of medicine.” He continues that its Republican proponents “opened the door to Koch brothers and Goldwater to rip apart the FDA, and then other government bodies after that.”

It’s important to recognize three things: 1) the FDA plays an enormous role in patient safety. Tearing up the regulatory framework, as Trump and his ilk favor, would have devastating consequences for health and well-being; 2) the history of granting desperate patients access to experimental drugs is one of offering false hope and enormous suffering; 3) the track record of the experimental drugs that the current legislation would support is mediocre.

The FDA approval process keeps us safe. When the FDA was first created in 1906, all it required was that drug labels accurately report the contents of medication. No longer was it permissible to sell “tonics” such as “Pinkham’s Vegetable Compound” or “Mrs. Winslow’s Soothing Syrup” without divulging on the label that the former contained alcohol and the latter morphine. 

The idea that FDA approval required that a drug be demonstrably safe and effective came much later. This amendments to the law were finally passed in 1938--after 5 years of debate--after the sulfa disaster of 1937: a liquid form of the new antibiotic, sulfa, had become widely available and was marketed for use in children. Because there were no safety tests performed, nobody seemed to have noticed that it was made with ethylene glycol (the active ingredient of antifreeze), a toxic chemical that causes liver failure and death—and that killed over 100 children. 

The requirement that drug companies actually perform randomized controlled trials to determine the safety and efficacy of proposed new drugs had to await the thalidomide disaster of the early 1960. Only after pregnant women treated with sleeping pills gave birth to babies with severe congenital malformations was were the Kefauver-Harris amendments to the FDA passed in 1962.

The track record of experimental drugs is poor. While the proponents of the new legislation, conservative groups such as the Goldwater Institute (named after Barry Goldwater) focus on “free choice” as the rationale for making untested substances available to the public, the widespread assumption is that substances entering a “phase III” clinical trial are all but proven drugs—just a few more bureaucratic hurdles, and they will be FDA approved. In fact, a phase III trial is designed to determine whether a drug that has shown some evidence of efficacy in a smaller, earlier trial (one that was focused primarily on looking for side effects) is actually effective. Many drugs that reach the Phase III stage do not move on in the approval process because they are not found to work. For cancer drugs, only 40% move ahead.

One of the most dramatic examples of the unfortunate consequences of premature access to an experimental therapy is the case of bone marrow transplant for advanced breast cancer. In the 1990s, more than 30,000 American women received bone marrow transplants at the cost of millions of dollars, extremely unpleasant side effects (including death—treatment-related mortality was reportedly as high as 15%). Insurance companies found themselves pressured to pay for the therapy—until several randomized controlled trials definitively demonstrated that it was no better than conventional chemotherapy.

The sad reality is that dying patients are vulnerable to claims that a cure is lurking around the corner. More often than not, what they are being offered is an opportunity to spend their dwindling resources on a bottle of false hope, often suffering enormously in the process. This is what the “right to try” legislation offers. The House and Senate versions must be reconciled for “right to try” to become law. Tell your senator to halt the assault on the FDA and keep drugs safe and effective.

Now Hear This!

This week I'm posting a podcast I did for GeriPal about my forthcoming book, "Old and Sick in America: the Journey through the Health Care System."

Is Heavy Metal Hip?

Type “metal-on-metal hip replacement” into your favorite search engine, and you will bring up dozens of hits from personal injury lawyers. These devices, initially touted as being more durable than conventional metal and plastic or metal and ceramic versions, have proved to be considerably less reliable. A substantial proportion produce problems within a few years after insertion: either the device fails, causing pain and disability, and needs to be replaced (necessitating another operation) or it sheds tiny metal flakes into the circulation, triggering both local inflammation and systemic illness. The British Orthopedic Association reported in 2011 that metal-on-metal (MoM) devices had a shocking 21% failure rate within 4 years and a 49% failure rate at 6 years. Several products have been taken off the market. The cost of replacing the joints is expected to reach billions of dollars in the coming years, and that doesn’t include the human suffering or lost productivity. What happened?

In discussing the perils of metal-on-metal hips, it’s critical to recognize that hip replacement surgery has been an enormous boon to aging Americans. Osteoarthritis, or wear and tear arthritis, is found in 50% of people over age 65, making it one of the most common chronic diseases of older people. It can cause pain and difficulty walking, debilitating symptoms that are often completely alleviated by replacing the worn out joint. And while hip replacement surgery has been around for decades, it has been plagued by the risk of hip dislocation or the artificial joint itself wearing out. Hence the holy grail of hip replacement surgery has been a hip made of better materials and with a better design. Metal-on-metal hip prostheses were once thought to be the answer to the orthopedist’s prayers.

Something else stimulated development of metal-on-metal hip joints as well as the desire for an improved device. With the benefits of surgery well established, the number of hip replacement operations remained fairly stable in the 1990s (adjusting for the aging of the population). Device manufacturers realized that if they could make a joint that lasted longer than the 15 years expected with conventional devices, they could increase sales by marketing to a younger population. Metal-on-metal hip prostheses, in which both the ball (femoral head) and the socket (acetabulum) are removed and replaced with metal parts, seemed to fit the bill; mechanical stimulation studies in the laboratory suggested they would last longer than existing devices.

The new MoM hips were rapidly introduced into practice and the total number of operations performed each year soared. Estimates from Kaiser Permanente, a large multi-specialty group practice that decided to keep track of all joint replacements in their patients, are that 35-40% of all joint replacements are now done in people under 65. Then anecdotal reports of early device failure began appearing. Device manufacturers initially denied any problems associated with MoM hips but in 2007, the Australian National Joint Replacement Registry reported a higher rate of hip revision surgery with MoM devices. Finally, in August, 2010, DePuy Orthopedics, a subsidiary of the giant Johnson & Johnson, recalled its MoM total hip implant system. A total of 90,000 people had had the device inserted, just about half of them in the US.

What is striking in this saga is that no randomized controlled trials comparing MoM hip joints to existing models were required for Food and Drug Administration (FDA) approval. Since the FDA considered these devices only “moderate risk” and since they regarded them as “substantially equivalent” to existing devices, only the most cursory approval process was necessary to bring them to market. High risk or radically new devices, by contrast, undergo rigorous pre-market testing, often involving sophisticated—and expensive—randomized clinical trials. To demonstrate “substantial equivalence,” all that’s required is to show that the new device has the same intended use as an existing device and the same technological characteristics. The FDA uses this expedited “510(k)” review process for an estimated 90% of the devices it approves. (A related surgical approach, but which did require a full premarket review, involves hip “resurfacing” rather than total hip replacement. This technique has also met with difficulties when the head of the femur is capped with metal rather than plastic, but it is not the subject of this article.)

In light of several well-publicized recalls of devices that entered clinical use via the 510(k) route, the FDA requested a review of the expedited review process. The review was conducted by the Institute of Medicine (IOM), a widely respected, not-for-profit, independent organization dedicated to providing advice to government policymakers. The IOM report was released last summer. Its conclusions were clear: “The committee finds that the current 510(k) process is flawed based on its legislative foundation. Rather than continuing to modify the 35-year-old 510(k) process, the committee concludes that the FDA’s finite resources would be better invested in developing an integrated premarket and postmarket regulatory framework that provides a reasonable assurance of safety and effectiveness throughout the device life.” Would this kind of approach, transparent and based on sound science, have avoided the MoM fiasco? \

If MoM artificial hips had been compared to existing products in a randomized controlled trial, flaws would likely have emerged early. While most of the device failures take five years to develop, much longer than the duration of a typical clinical trial, data from the British National Joint Registry suggest there are signs of trouble much earlier. For women aged 60-69, the Registry the revision rate for cemented hips one year after initial insertion is .65%; the revision rate for metal on metal hips in this population is 1.42%, or more than double. By year three, the gap is even more impressive: 1.32% of cemented hips require revision compared to 4.11% of MoM joints, a near tripling of the rate.

Adequate pre-market testing would have raised red flags; systematic post-market surveillance, which is non-existent in the US, would have revealed any problems that had escaped early detection. The Australians, who maintain a Registry of all the artificial joints inserted in their population, observed a spike in surgical revisions after hip replacement in 2007, with the highest revision rates in MoM joints, and the British reported a similar finding based on their Registry soon afterwards. A US database, which would have been far larger, might have detected problems even more quickly.

Any rational observer would conclude that our story will have a happy ending: the recommendations of the IOM committee will be implemented by Congress, we will have a new improved regulatory process for medical devices. Tales such as the metal-on- metal hip fiasco will provide fodder for future historians who will write of the bad old days when corporate greed and medical wishful thinking led to needless suffering in hundreds of thousands of patients, at a cost of billions. But the reality is strikingly different. The IOM report was dead on arrival. In a shocking development, the report was viciously attacked even before it was released. As the NY Times put it in a July 27, 2011 article: “Allies of the medical device industry are waging an extraordinary campaign in Washington to discredit a coming report by one of the country’s pre-eminent scientific groups.” The article continued that business groups took “the highly unusual step of making a pre-emptive strike,” claiming that better regulation would “slow innovation, harm patients and cost jobs.” Industry does not want to modify the 510(k) process, substituting more thorough, time-consuming, and costly studies of potentially risky devices. Their lobbyists responded to the IOM report by barraging the media, Congress, and other thought-leaders with a blistering counter-attack. The result? Deafening silence in the halls of Congress, which would need to pass legislation to further amend the Food and Drug Administration Act.

The metal on metal hip story is not unique. A recent article in the Archives of Internal Medicine reviewing all FDA device recalls between 2005 and 2009 found that 71% of the devices recalled because they were felt to cause serious health problems or death had been approved by the 510(k) expedited review process. Patients who have been harmed by dangerous devices are busily trying to salvage their own health and are relying on the courts for monetary compensation for their injuries. But it is consumers who put pressure on government back in 1976 to demand regulatory protection from dangerous devices. It was consumers, reacting to dramatic examples such as deaths related to the Dalkon Shield, an intrauterine contraceptive device, who demanded and finally prevailed upon Congress to pass the Medical Device Amendments of 1976, for the first time giving the FDA jurisdiction over devices. How many more disasters will we need before we act again?

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.

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.

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.

Drugged in the Nursing home

This week’s Boston Globe featured an article blasting Massachusetts nursing homes for having too many residents on antipsychotic medication, “Nursing home drug use puts many at risk.” It portrayed vulnerable grandmothers as sedated, mute, and drooling, transformed by drugs into tragically diminished versions of their earlier vivacious selves. The headline could have been from the 1970s when Mary Mendelson wrote her muckraking book, “Tender Loving Greed,” pillorying the nursing home industry. Has nothing changed in the last 30 years?

A great deal has changed. In the 1980s, Congress responded to the deplorable state of nursing home care with the Nursing Home Reform Amendments, part of the Omnibus Budget Reconciliation Act of 1987 (OBRA-87).This major piece of legislation sought to make nursing homes free of both physical and chemical restraints. And to a large extent it worked. Translated into regulations in 1991, OBRA-97 led to enormous declines in the use of antipsychotic as well as other “psychoactive” drugs such as benzodiazepines.

Then new, “atypical” antipsychotic medications came along. Touted as equally effective but less toxic, risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) appeared with growing frequency in nursing homes. Physicians were mandated by OBRA-87 to monitor the use of these drugs—to look for side effects such as Parkinsonian symptoms or drops in blood pressure. They were also supposed to limit prescription of these new drugs, along with other old fashioned or “typical” antipsychotics such as haloperidol (Haldol), to well-defined situations. The drugs were to be used for chronic schizophrenia and for dementia with psychotic features, unresponsive to alternative treatment. As the prevalence of dementia in nursing homes increased, so too did the prevalence of behavior problems: kicking, biting, smearing feces, and screaming. Less dramatic but nonetheless challenging were other behaviors that were also on the increase, such as pacing, wandering into other residents’ rooms, and urinating in trash cans. These behavioral disturbances wee extremely difficult for nursing home staff to manage. Convinced that the new “atypical” antipsychotics were the solution, physicians prescribed more and more of these drugs.

Some residents did improve. Most of them were not transformed into zombies by the medication. But the behavioral symptoms of dementia often come and go without pharmacological intervention. While many physicians were confident they were seeing a benefit of the drugs, others were not so sure. A large randomized trial
found that all three of the leading antipsychotics were equally effective in controlling symptoms—and indistinguishable in efficacy from placebo.

Nursing home physicians were skeptical. The study was conducted among outpatients. Maybe long term care residents were different from outpatients—surely they were more demented and had worse symptoms. But at around the same time came other disturbing news: the atypical antipsychotics were associated with a risk of sudden death. The FDA issued a new “black box” warning to physicians prescribing these drugs,followed 3 years later by another black box warning against using the older, “typical” antipsychotics. The drugs were not prohibited, but sober commentators advised prescribing them with great caution, restricting their use to patients with longstanding psychiatric illness and checking an EKG before and after starting the drugs.

In the face of all this bad news, how can it be that a recent study of over 16,000 nursing home admissions found that 29% received at least one antipsychotic over the course of a year? Of these, just about one-third had no identified clinical indication for the drug. Residents admitted to nursing homes with the highest baseline prescribing rates of antipsychotics were 1.37 times more likely than those admitted to nursing homes with the lowest baseline rates to receive a new antipsychotic prescription in the coming year.

Over-use of antipsychotics in the 1970s and 1980s was bad enough. In the intervening years, we have had regulation (OBRA-87), scientific studies of both efficacy and toxicity, and warnings from the FDA. What is going on?

The problem is that agitated behaviors in demented nursing home residents are a major challenge. There is no simple solution. Staff training can help. Increased staff: patient ratios can help. But with the rise of alternative options for care such as assisted living and a decline in the total number of people living in nursing homes, those individuals who do live in a nursing home tend to be more demented and have greater behavioral problems than ever before: in 2007, 69% of US nursing home residents had cognitive impairment, with 42% diagnosed with moderate to severe impairment. Solving the problem of how to care for demented nursing home residents will require far more sweeping changes than adding a few in-service programs for staff or hiring a few more nursing aides. The key is culture change.

To understand the role of culture change, we should look at the use of feeding tubes in nursing home patients with advanced dementia. The feeding tube story is in many ways similar to the antipsychotic medication story: the practice persists despite studies showing that feeding tubes do not prolong life, they do not prevent aspiration pneumonia, and they do not promote healing of pressure ulcers, the reasons given for their use. There is tremendous state-to-state variability in the use of feeding tubes. And while studies have identified a variety of institutional factors associated with feeding tube use (for-profit status of the nursing home, absence of advance care planning discussions, speech therapist on staff), there has been no deep understanding of why the rates vary so dramatically.

In the very same issue of the Archives of Internal Medicine that reported on the national use of antipsychotic drugs in nursing homes, Susan Mitchell and her colleagues presented an ethnographic study of two nursing homes to explore the role of nursing home culture in promoting the use of feeding tubes. In one nursing home, 42% of residents with advanced dementia had feeding tubes while in the other nursing home, only 11% had feeding tubes. The study found startling differences between the cultures of the two institutions. The low use nursing home had a home-like environment, specially trained nursing assistants, and lots of family involvement in decisions of the goals of care. The high-use facility, by contrast, had an institutional atmosphere, inadequately trained nursing assistants, and a focus on regulatory compliance rather than quality of life.

Preliminary evidence suggests that the same nursing homes that foster a culture conducive to hand feeding rather than tube feeding also have a low use of antipsychotic medications. Providence Mount St. Vincent’s, a nursing home in Seattle, Washington that pioneered the culture change model, reported a 100% decrease in the use of antipsychotic medications. If this is confirmed, it will provide compelling evidence that what matters most to nursing home residents, beyond rules and regulations, is designing a community that is patient-centered, where staff are cross-trained to provide multiple tasks, and that focuses on relationships. It is in homes like this that even individuals with advanced dementia may be able to flourish without either feeding tubes or antipsychotic medications.

The Heart of the Matter

Just before the annual deluge of holiday visitors began inundating the Magic Kingdom, over 20,000 people gathered in Orlando, Florida to attend the American Heart Association annual meeting. At one late-breaking scientific session, Dr. Joseph Rogers, a Duke University cardiologist, presented the results of a study of a nifty new cardiac device, the HeartMate II (to distinguish it from its predecessor, HeartMate I, also known as HeartMate XVE). This remarkable 390-gram contraption is the next best thing to a heart transplant for patients with severe heart failure. It is a “ventricular assist device,” (VAD) implanted in the abdomen, hooked up to the heart to propel blood through a failing ventricle, and powered by an external generator. The study, published the very same day in the online version of the New England Journal of Medicine, showed that patients with the new device lived longer and better, with fewer complications, than those who got the earlier variety.

Just six years ago, the Centers for Medicare and Medicaid Services (CMS) approved use of the HeartMate I in Medicare patients as “destination” or definitive treatment of severe heart failure. Based on the results of a 2001 study, the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) trial, CMS concluded that the device was “reasonable and necessary” for the treatment of advanced heart failure and therefore, as required by its 1965 Congressional mandate, agreed to pay for implantation of the device.

Physicians, however, were not convinced the device was reasonable or necessary. In fact, the number of patients receiving a ventricular assist device has fallen every year since CMS approved its use. Between March, 2006 and June, 2009, a total of only 1664 HeartMate I’s were implanted (just under 500 per year) and 90% of them were used as “bridge to transplant,” that is to tide patients over until a heart became available for transplant, rather than as “destination therapy,” or permanent treatment. Physicians evidently were not impressed by the data that patients who had a ventricular assist device lived longer than those receiving “maximal medical therapy.” Even with the device, one-year mortality remained high at 48% and two-year mortality at 77%. Moreover, HeartMate I recipients were at risk of stroke, infection, and device malfunction.

Will physicians be more enthusiastic about the new HeartMate II? It is smaller—small enough to fit into a woman, unlike the earlier version. It uses a continuous rotary system rather than a pulsatile mechanism, which means it’s quieter and more durable. And the new device is clearly superior to the old one—the randomized study reported in Orlando found that 46% of those with the new device were alive after 2 years without having sustained a debilitating stroke or required replacement of the device, compared to 11% of those who got the original model. Quality of life was also improved, with recipients of the new HeartMate able to walk further and do more for themselves.

Are these results good enough? They will almost surely be good enough for the Food and Drug Administration to approve use of the device as destination therapy and for Medicare to follow suit by approving reimbursement in Medicare patients—currently Medicare pays an average of $177,000 for a hospitalization in which a ventricular assist device is inserted. Whether physicians will regard the new pump as ready for prime time remains to be seen.

The deeper question is whether we should be putting more and more resources into shoring up failing hearts in patients near the end of life or whether, instead, we should concentrate on palliative care for patients dying of heart failure and on prevention to avoid the development of heart failure in the first place.

Palliative care is an effective, well-regarded approach to end stage heart failure. It focuses on comfort and on supporting patients and their families as the end draws near and may involve enrollment in hospice. Individuals whose heart cannot pump properly repeatedly suffer from fluid backing up into their lungs, swelling their legs, and filling their abdomen, causing shortness of breath, difficulty walking, and fatigue. Instead of hospitalizing these patients, often transferring them to the Intensive Care Unit where they may be attached to a ventilator that forces oxygen into their lungs and put on an intravenous drip to try to stimulate the heart to contract more forcefully, palliative care strives to keep them home. At home they use oxygen and medication such as morphine to help them breathe. Interestingly, the studies of the left ventricular assist device compare patients receiving one particular device to those getting another type (the new study) or patients receiving a device to patients receiving “maximal medical therapy” (the earlier study), but never compare patients receiving a device to those getting palliative care.

Prevention makes a lot of sense in the case of heart failure. Heart failure is the leading cause of hospitalization in individuals over age 65. Americans have a 20% life time risk of developing the condition and treatment costs the US upwards of $30 billion per year. But we know what causes the heart to fail: it is high blood pressure, diabetes, or coronary artery disease (which in turn is caused by some combination of high blood pressure, diabetes, high cholesterol and smoking). And every one of these predisposing conditions is treatable or preventable. While there are few good studies of what it would cost to institute a comprehensive set of measures to prevent heart failure, we do know that 82% of the cardiac events in one observational study, the Nurses Health Study, were attributable to diet and lifestyle issues. An Australian analysis suggests that the best way to prevent heart failure is by a combination of medical preventive strategies (proceeding patient by patient to assess risk factors and intervene to treat high blood pressure, diabetes, and high cholesterol) and public health strategies (using legislative and environmental approaches to promote a healthy lifestyle).

America has its heart set on the technological fix—the HeartMate II is the latest in a series of ingenious approaches to treating the chronic diseases afflicting older people. But its time to get to the heart of the matter, trying to prevent the major scourges that we have the knowhow to avoid, and palliating those who, despite our best efforts, are dying.