Deja Vu All Over Again?

 

The big news in geriatrics this week was the FDA  approval granted to a drug against Alzheimer's disease, the first new drug in 20 years. It reminded me of the day in 1986 when the initial report about what would be the very first FDA-approved drug against this disease appeared.

It was November 13, 1986 and I had been a practicing geriatrician for four years. My weekly copy of the New England Journal of Medicine had arrived right on time, as it did every Thursday. I scanned the table of contents and one article immediately jumped out at me. It had the suitably serious, scientific-sounding title “Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.”

 

During four years  of clinical practice—plus a year of geriatrics fellowship and three years doing an internal medicine residency—I had encountered patients with what we then called “SDAT,” (senile dementia of the Alzheimer’s type) and which we now simple call Alzheimer’s disease. The cognitive impairments of dementia were to me, to family members of the afflicted, and often to the affected themselves, among the saddest of the many disorders that develop among older individuals. Death, while also very sad, was part of the natural order of things, especially when it came after a long and rich life. But dementia in general and Alzheimer’s disease in particular was devastating because it attacked personality; some would say it assaulted personhood itself. While I would go on to spend much of my career thinking about how best to enable people with dementia (as well as those with physical frailty) to live meaningful lives despite their limitations, I recognized then and continue to believe today that the condition is a scourge that we should strive to prevent, eradicate, or at least ameliorate.

 

The medication described in the 1986 NEJM article would ultimately be approved by the FDA under the name of Tacrine for treatment of mild to moderate Alzheimer’s disease; it would be supplanted by its first cousin, the drug donepezil, brand name Aricept; and Aricept would top $2 billion in US sales by the time it came off patent in 2013. The story of the drug’s development says volumes about Americans’ desperation for a medical fix to Alzheimer’s, about big business, and about our regulatory system. Both the similarities and the differences between the Tacrine story and the tale of the new drug approved by the FDA for the treatment of Alzheimer’s are illuminating.

That 1986 study ostensibly showing that Tacrine led to improvements in cognition as well as to overall functioning was based on a whopping 17 patients, only 14 of whom actually completed the study. Its lead author was Dr. William Summers, a psychiatrist at UCLA medical center who had never before published anything of importance and had done very little research altogether. The scientific community immediately began questioning not only Summers’ credibility but also his methodology. Did the 17 patients actually have compelling evidence of an Alzheimer’s diagnosis? Did the “global assessment rating” used to measure outcomes translate into meaningful improvement?

 

After Summers filed for FDA approval for his drug,the FDA investigated Summers and his lab. The agency issued a rare “interim report” in 1991 in which it criticized Summers for the absence of documentation that the study was actually performed as  claimed in the NEJM  paper.  It questioned the randomization process and whether the physicians were, as asserted by Summers, blinded to what drug the patient was receiving. The best the FDA could say was that there was “no clear evidence of purposeful misrepresentation.”

 

In response, the public vilified the FDA, claiming the agency was “heartlessly impeding the relief of suffering.” David Kessler, the FDA director, received hate mail.

 

Approval of the drug came, but only after the release in 1992 of a larger more carefully conducted study by the “Tacrine Collaborative.” The trial lasted for 12 weeks and was carried out at 23 centers involving 468 patients. The results, published in the Journal of the American Medical Association, showed a statistically significant improvement in cognition and in overall function, whether measured by physicians or caregivers. And so, the first drug was approved for treatment of Alzheimer’s disease. Sales soared.  But questions continued to plague use of the drug—a subsequent study, for example, testing the effectiveness of a higher dose of the drug,  found that the higher dose was more effective than lower doses—but more than 2/3 of the patients dropped out of the study. Tacrine was soon effectively replaced by donepezil (Aricept), another cholinesterase inhibitor that differed only from Tacrine in that it is taken once a day rather than twice and has fewer gastrointestinal side effects. Patients and families demanded these drugs, which were soon followed by chemically slightly different but no more effective agents such as Excelon; the drug companies advertised them widely and made a small fortune on their  sales; but clinicians remained skeptical. I, for one, believe that the cholinesterase inhibitors are next to useless. None of the numerous studies of the drugs carried out since 1986 have persuaded me otherwise.

 

Fast forward to 2021 and the approval by the FDA of aducanumab under the brand name of Aduhelm. This is a completely different kind of treatment. Tacrine and Aricept are cholinesterase-inhibitors: they work by increasing the level of the neurotransmitter, acetylcholine, which is dramatically reduced in Alzheimer’s. They are given orally and were never terribly expensive, although Aricept got cheaper when the generic version became available. Side effects, particularly in the case of Aricept, are modest and consist of nausea and very rarely of liver enzyme abnormalities.  The new drug, by contrast, is a monoclonal antibody that works to mop up deposits of beta-amyloid from the brain, the chemical widely thought to cause Alzheimer’s disease. It must be given intravenously once a month. The average yearly cost will be set at $56,000. Two years ago, its manufacturer, Biogen, stopped an ongoing clinical trial of the drug after interim analysis failed to demonstrate efficacy. The drug company then re-analyzed the data and claimed it was effective after all, but an FDA Advisory Panel, convened in  November, 2020 unanimously concluded there was insufficient evidence of significant benefit to proceed. 

 

Multiple other monoclonal antibodies targeting beta amyloid have also failed, leading some to suggest that by the time these drugs are given to patients, it’s already too late. Or maybe beta amyloid is a marker for the disease and not the cause of the disease. It is in this setting, that the FDA approval of aducanumab is something of a surprise.

What is particularly striking about today’s FDA approval is that it is not based on the clinical effectiveness of the drug. Rather, it is based on its ability to clear the brain of amyloid deposits. There is a long tradition of requiring that drugs cause improvement in clinically meaningful outcomes, not just in “surrogate markers.” Cholesterol-lowering drugs were approved based on their ability to prevent heart attacks, not just on their ability to lower blood cholesterol levels. Antihypertensive drugs were approved based on their effectiveness in reducing strokes, not just on their capacity to lower blood pressure. To be sure, the FDA is holding off on full, unconditional approval until it sees the results of a yet to be performed large clinical trial demonstrating long-term benefit of amyloid plaque reduction. In the meantime, anxious patients and their families will submit to monthly injections of a drug that has been shown to cause symptomatic brain swelling, manifested by nausea, vomiting, visual problems, headaches and sometimes small strokes, in 40 percent of cases. 

We are a long way from the trials and tribulations of tacrine, but in the end, is the tale of aducanumab any less disturbing? In both cases, there was enormous pressure by the public to approve a drug that offered hope, some hope, however slim, of ameliorating this terrible disease. In both cases, the FDA, after seemingly acting based on scientific considerations alone, seemed to succumb to external pressures. And in both cases, the pharmaceutical industry stood to gain enormously by release of the drug. The FDA currently has an acting director: President Biden has yet to name a new, permanent head. Maybe it's time for the FDA director to become a civil servant, selected by the FDA members, rather than a political appointee. At the very least, the new director, when chosen, should take a long hard look at decision-making within the organization.

Beer(s)

I haven’t written a blog post in a while. Not because I’ve been ill or travelling, but simply because I couldn’t find anything I was interested in writing about. Now, at last, I came upon some appropriate material. Next week I hope to blog about Katy Butler’s new book, The Art of Dying Well. This week I want to say a bit about the “2019 American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.” 

The Beers criteria were first promulgated in 1991 by Mark Beers and published in the Archives of Internal Medicine. The idea of reviewing the literature on adverse drug reactions in the elderly and publicizing a list of the worst offenders was widely applauded—but the methodology used in the original list was severely criticized. The American Geriatrics Society subsequently adopted the project and has been responsible for recent revisions. The newest list was just issued.

As with earlier AGS revisions, the expert panel charged with evaluating medications used evidence-based criteria for its judgments. For every medication about which it makes a recommendation, it indicates the quality of the evidence and the strength of the recommendation. Moreover, the panel distinguishes among three groups of potentially inappropriate medications: 1) those that should be avoided by older people in general, either because of a high risk of adverse effects, limited effectiveness, or the availability of better alternatives; 2) those that should be avoided by people with certain medical conditions (for example, renal failure); and 3) those in which the risks generally outweigh the benefits but which may be useful for particular individuals.

Physicians should keep all the tables on hand as a reference; because the medications are sorted by therapeutic category, i.e. “anti-infective” or “cardiovascular” and only generic names are used, the list is less useful for patients and families. I am going to summarize some of the main points for the general reader.

One group of medications that the AGS strongly recommends avoiding (although interestingly, the quality of the evidence is rated as “moderate”) are the first- generation antihistamines, drugs such as diphenhydramine (benadryl) and hydroxyzine (atarax) that are used against allergies and itching. They cause dry mouth, constipation, and confusion. To a large extent they have been replaced by the second-generation antihistamines (fexofenadine or Allegra, loratadine or Claritin, and cetirizine or Zyrtec) and their isomers, sometimes called third- generation antihistamines (levocetirizine or Xyzal). 

A number of first-generation antidepressants are similarly to be avoided because they, like the antihistamines, are anticholinergic (amitriptyline or Elavil, imipramine or Tofranil, and desipramine or Norpramin)—though in this case the quality of the evidence is high. These drugs have largely been superseded by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs including fluoxetine or Prozac, citalopram or Celexa, and sertraline or Zoloft) and serotonin and norepinephrine reuptake inhibitors (SNRIs such as duloxetine or Cymbalta and venlaxafine or Effexor). It’s important to note that all these drugs can cause confusion; a few highly publicized studies notwithstanding, the AGS does not claim that any of these medications actually cause dementia. It’s also worth commenting that while all the antihistamines are available over the counter, so older patients might mistakenly choose one of the first-generation drugs over less toxic agents, the antidepressants are all prescription drugs and the first-generation agents are very seldom prescribed by physicians.

A second group of medications that AGS singles out are the antipsychotics, both the first-generation variety (drugs such as haloperidol or Haldol and fluphenazine or Prolixin) and second-generation agents (olanzapine or Zyprexa, quetiapine or Seroquil, and risperidone or Risperdal). All these drugs are deemed risky and are to be avoided except in people with schizophrenia or in people with dementia who are exhibiting dangerous behavior that has failed to respond to other alternatives. This is important because physicians continue to prescribe antipsychotics for the behavioral manifestations of dementia, despite compelling evidence that they are ineffective and/or risky.

Finally, both the benzodiazepines (used to treat anxiety or sleep disorders) and non-steroidal anti-inflammatory pain medications (drugs such as ibuprofen or Motrin and naproxen or Naprosyn but not celecoxib or Celebrex) receive an “avoid” recommendation, though in both cases the quality of the evidence is moderate but the recommendation is deemed strong. This is noteworthy because both groups of medicines continue to be prescribed by physicians and many of the second group are available over-the-counter.

The newest iteration of the Beers list is not perfect. But at the very least, there should be an awfully good reason for an older person to take any of the drugs the AGS says to avoid.

Putting the Genie Back in the Bottle

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

discuss this phenomenon, calling it “the undiffusion of established practices.”

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

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

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

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

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

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

No Quick Fix for Mortality

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

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

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

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

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

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

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

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

Is Medicare on the Mend?

A buoyantly optimistic Paul Krugman proclaimed recently that Medicare’s woes are over—after a long period of seemingly relentlessly rising costs, costs that were rising so fast that they were clearly the major threat to the federal budget, Medicare per beneficiary expenditures actually fell last year. Economics guru and NY Times editorialist Krugman argues that the good news cannot simply be attributed to the recession because Medicare is a government program and therefore recession-proof. Now it’s dangerous to take issue with a force such as Krugman.  But I want to at least raise the possibility that Medicare expenditures are not immune to the economic downturn because of the large amount of money that Medicare beneficiaries pay out of pocket for health care. And if a patient doesn’t get a drug prescription filled, for example, because his co-pay is too high, then Medicare does not have to pay for that drug, and expenditures fall. In this vein, a report released in July by the Henry J. Kaiser Family Foundation, “How much is enough? Out-of-pocket spending among Medicare beneficiaries: a chartbook” is very sobering.

The main findings of the report (see chart in previous post) are that fee-for-service Medicare recipients spent an average of $4734 out of pocket for health care in 2010, up from $3253 in 2000--a 44% increase. Most of that spending is by those age 85 or older: they spent an average of $5962 out of pocket compared to only $1926 for those ages 65-74.  And older people with 3 or more “ADL deficits,” or difficulties carrying out basic daily activities, spent a mind-boggling $9200 on health care, mainly on services. Out of pocket spending went to items such as Medicare premiums, other supplementary insurance, and long term care. In addition, 11% went to paying for prescription drugs as Medicare Part D has evolved since its inception to include more and more cost shifting to patients.

Interestingly, my colleagues at the Harvard Pilgrim Health Care Institute, just published a study in Health Affairs in which they present data indicating that older patients are increasingly skipping pills, taking less than the prescribed doses of medicines, or failing to fill prescriptions altogether in order to save money: among patients with 4 or more chronic conditions, they found that while 14.9% experienced “cost-related medication nonadherence” in 2005, this rate fell steadily until it reached 10.2% in 2009, and then it began rising again, reaching 10.8% in 2011.

So it is entirely possible that the fall in Medicare costs reflects at least in part decisions made by patients to forgo particular pricey interventions. The result, predictably, would be savings to the entire Medicare program. Now whether such choices made by patients adversely affects their health is another matter.  The Health Affairs study assumes that non-adherence to medications is likely to lead to adverse health outcomes including worth health states and increased rates of hospitalization, especially in older individuals with multiple chronic conditions. They base their assumption on studies from the 1990s, principally conducted in the mentally ill and in Medicaid patients, that in fact showed that when patients did not take their medicines as prescribed, their clinical condition deteriorated. Whether the same would hold true for chronically ill older patients today is not so clear: there is ample evidence that older individuals with multimorbidity are at increased risk of adverse drug reactions the more medicines they take and that following the guidelines for all the diseases they have can cause falling, fainting, confusion, and other problems. Nonetheless, it would be preferable for physicians to make wiser prescribing decisions based on an understanding of physiology rather than leaving it to patients to decide which medications to forgo based on cost.

Medicare expenditures are falling and it behooves us to understand exactly why and to evaluate the consequences. Whether the cost saving strategies of the Affordable Care Act are responsible, and whether the particular decreases in costs have had any effect on patients’ health and well-being, is yet to be determined.

Acronyms of Doom

When I was in medical school, U.S. hospitals were plagued by only one kind of “superbug” or antibiotic resistant bacteria. Methicillin-Resistant Staphylococcus Aureus, abbreviated as MRSA and pronounced “mursa,” was the Enemy and it had been around since the early 1960s. I remember the yellow precaution signs on the door of rooms housing patients infected with this organism and the ritual donning of a yellow gown and surgical gloves before entering those rooms. Staph colonizes the skin of healthy people; if it enters the body through a break in the skin it can cause a serious infection, and if the staph is resistant to what was previously the best drug for treating it, the patient can be in trouble.

Then in the late 1980s, along came another bad actor, Vancomycin-Resistant Enterococci (VRE). Enterococci normally inhabit the gastrointestinal tract; sometimes they escape and when they do, for example through fecal contamination of a wound, they can cause significant mischief. Enterococcal infections had come under control with the antibiotic vancomycin—until they developed resistance. Now, MRSA and VRE have been joined by a new threat: Carbapenem-Resistant Enterobacteriaceae (CRE). According to a study published this month, the rate of detection of this infection has jumped five-fold in 5 years. And the mortality from these infections ranges from 48% to 71%. The Centers for Disease Control and Prevention (CDC) in Atlanta took the extreme measure of classifying CRE as an urgent threat. Only 2 other organisms currently share this honor.

The newest superbug, like MRSA and VRE before it, is something that healthy people don’t normally contract. Its victims are patients in nursing homes and hospitals, especially people who are connected to a medical device such as a ventilator or a catheter (whether urinary or intravenous). Debilitated older people are at particularly high risk. The CDC offers a 4-prong strategy for attacking the problem (preventing infection in the first place, tracking resistant organisms, improving the use of today’s antibiotics, and promoting the development of new antibiotics). I suggest an additional strategy that is rarely discussed: keeping frail, old people out of the hospital altogether.

From the time that the hazards of hospitalization were first recognized 50 years ago, the main way doctors have proposed dealing with them is to try to make hospitals safer. Old people become confused in the hospital? Don’t give them sedating medicines that make them confused. Old people fall in the hospital? Use bed alarms and chair alarms to alert nurses that they are getting up. These tactics and others can be helpful, but they don’t eliminate the dangers of the hospital and some interventions, such as side-rails on hospital beds, increase rather than decrease risk. Similarly, our first impulse as we try to control superbugs such as CRE is to reach for the precaution gowns to keep nurses and doctors from spreading the germs. Because antibiotic resistant bacteria are so great a problem, we need to respond with a multi-prong strategy. So yes, educating physicians to use antibiotics judiciously (preventing the development of resistance in the first place) and encouraging pharmaceutical companies to design new effective antibiotics are important. But let’s not forget that in most cases, the patient would not have gotten the infection if he or she hadn’t been in the hospital—these are generally hospital-acquired infections, not the reason for the hospitalization. Sometimes, frail old patients can be treated satisfactorily outside the hospital. Finding an alternative to hospital care is a way to avoid a growing list of “adverse reactions to hospitalization,” including delirium (acute confusion), incontinence, falls, and all those acronyms spelling doom, MRSA, VRE, and now CRE. 

A Tale of Two Medicines

Imagine two versions of a medication that are essentially identical but one costs 100 times as much as the other. Using the more expensive variety enriches the drug company that manufactures it and the doctors that administer it—with patients and the American people paying the price. Yet that’s exactly what’s happening with two drugs that are used to treat a form of macular degeneration and diabetic macular edema, 2 common conditions that cause blindness, principally in older people. And the reason this is happening is the steadfast refusal of Congress to allow Medicare to consider cost in making reimbursement decisions.

The story came to light when Medicare released data in April about how it spends its money. It turns out that eye doctors are among the physicians who get more than a million dollars a year from Medicare. The reason: they inject the drug Lucentis (ranibizumab) into the eyes of their patients, an effective treatment for macular degeneration or macular edema, and are paid the average price of the drug plus 6% overhead by Medicare. They could, however, inject a far cheaper version of the drug, using the chemotherapy agent Avastin (bevacizumab) off-label. In absolute dollars, Lucentis costs $2023 per dose and Avastin costs $55 per dose. And a typical patient is treated up to 12 times per year, sometimes for years.

It turns out that that National Institutes of Health (NIH) actually funded a study of over 1000 patients comparing treatments for the more common of the 2 eye conditions for which the drug is used, neovascular macular degeneration. The study found no difference in effectiveness between the 2 drug variants, Lucentis and Avastin. Not enough patients were enrolled to determine if there are statistically significant differences in safety. That is, it’s possible that one version of the drug is safer—and since a compounding pharmacy has to convert the chemotherapy drug Avastin into the drug used by eye doctors, this is a theoretical possibility—but we don’t know for sure. Subsequent studies have found minor differences in the safety profiles of Avastin and Lucentis, which are both made by the same drug company.

Carefully performed modeling of what we can expect over the next 10 years—making reasonable assumptions about how common the eye conditions will be, how beneficial treatment is likely to be, the extent of side effects—shows that if current practice patterns continue, in which 2/3 of people are treated with the cheaper drug and 1/3 with the costlier drug, then Medicare will spend $20 billion on these 2 treatments and patients will spend $5 billion (on co-pays). If, however, everyone started using the cheaper drug, then Medicare would spend only $2 billion and patients only $420 million. And if everyone switched to the more expensive drug, Medicare would spend $57 billion and patients would spend $14 billion. So what should we do?

A recent opinion piece in JAMA suggests that Medicare, which is currently prohibited from negotiating over drug prices, could get around this problem by using a technical loophole. It can exercise flexibility in how it figures out how much to pay for a product or service if the current payment amounts are “inherently unreasonable because they are either grossly excessive or deficient.” To date, this process has never been invoked in paying for medications.

The article in Health Affairs describing the predictive model suggests that Medicare could selectively increase reimbursement to doctors who use the cheaper drug or that Congress could modify the regulations for “biosimilars” (as the generic versions of biologically complex drugs such as Lucentis are called). All these approaches take as a given that for Medicare to spend 1/6 of its entire Medicare Part B budget on one drug is absurd. Just how absurd becomes apparent if we look at the cost-effectiveness of Lucentis: medical costs would go up $2 million/QALY (quality-adjusted life year) if everyone took Lucentis instead of Avastin, though most health economists consider $50,000-$100,000/QALY a reasonable amount to pay.

What all this tells me is that it’s time we stop pretending that cost-effectiveness analysis is unethical. Spending $25 billion in 10 years when we could achieve the same end by spending $2 billion is what’s unethical. Comparative effectiveness research, which is supported by the Affordable Care Act and which forms the foundation of the new independent research agency, the Patient Centered Outcomes Research Institute (PCORI), is legally prohibited from considering cost. But if we don’t start considering cost explicitly, we will pay dearly in the not so distant future.