December 17, 2018

Insuring You Have Insurance

It was really outrageous. It sheds light on our crazy health insurance system—and it is a warning to anyone considering going without health insurance or who thinks mandatory insurance is unnecessary. Here’s what happened:

A family member recently received an “explanation of benefits” from his insurer. He had had had a CT scan for which the hospital performing the test charged $1717. Leave aside for a moment that this is a preposterous fee. He was billed $237.21. Why the difference? The difference was due to the “discount” he received because his insurer had negotiated a rate with the hospital that was 14% of the rate the hospital wanted to charge. The insurer didn’t actually pay a cent—my relative has a “high deductible plan” and has to pay all medical fees until he his family has spent $5000 in a given year. But because he has insurance, he had to pay $237, not $1717. Put differently, if my relative didn’t have health insurance, he would have been charged the full $1717 for exactly the same test.

The system is a bit like scalpers charging extraordinarily high rates for tickets to popular shows or sports events. As long as the system of multiple private insurers is in place, where each insurer negotiates its own deals with “providers,” it’s terribly important to have insurance. If you don’t, you’ll be scalped.

With the Affordable Care Act once again under siege, it is critical to remind everyone why having health insurance matters. This is important for the over-65 population even though virtually everyone over 65 qualifies for health insurance in the form of Medicare. It’s important to older people because their caregivers tend to be under 65: if they get sick and don’t seek treatment because they lack insurance, they won’t be able to serve as caregivers. And it’s important because if those who are not quite old enough for Medicare don’t have private insurance, they may opt to defer taking care of medical problems until they reach 65. This then puts a significant strain on Medicare when they do enroll, potentially raising the cost of the program and putting it in jeopardy.

Mandating that everyone have health insurance makes sense because insurance is only viable if low-risk individuals subscribe along with those at high risk. If sick people are the only ones who buy health insurance, it will become inordinately expensive. Imagine, for example, that nobody bought car insurance until after they had a car accident—and then they expected the insurance to kick in immediately. Then the only people paying a premium would be those who filed claims. The insurance company would have to charge rates that were high enough to make good on all the claims—which means you would probably end up paying the same amount for your policy as you would have paid to fix your car—or to cover the costs of medical care for anyone injured—after an accident.  In the case of health and disease, insurers can get around this problem by deciding that if people wait until they get sick to buy insurance, they won’t be covered for precisely the condition that led to their deciding to insure!

Just keep in mind, that in addition to all these reasons for everyone having health insurance, there’s one more. As long as we have a system of private insurers that negotiate rates with health care “providers” (hospitals, physician groups, etc.), you will pay much less for medical care if you have insurance than if you don’t, even if your insurer pays nothing at all. If this seems absurd, it is, but that is how the system works.

Now, there are other ways to address this problem other than exhorting or requiring everyone to purchase health insurance. We could give everyone health insurance—as is done with Medicare Part A for people over 65—and use tax revenues to pay for the policy.  Medicare sets rates (as long as it has a monopoly, it doesn’t have to negotiate with each provider individually) and in many states, providers are required to “accept assignment.” That means your doctor cannot turn around and bill you the difference between what they charge and what Medicare pays them. But in the current world, you go without health insurance at your own peril.

December 02, 2018

How We Die

The data are out: in 2017, the opioid epidemic took even more American lives than in any previous year: a record 72,000 people died of an opioid overdose. As we struggle to figure out how to deal with this problem, it seems more important than ever to remember that opioids--morphine and its cousins--when used appropriately, can also be life giving. This is particularly true near the end of life, and one setting where people often receive such opioids is hospice care. Why are opioids beneficial in this setting and how can abuse be avoided?

For starters, we need to recognize that not everyone who is in the last phase of life needs opioids. Patients enrolled in hospice, for example, who typically have a prognosis of six months or less (the commonly used eligibility criterion) have a wide variety of diagnoses.  Of the 1.43 million Medicare patients enrolled in hospice in 2016 (only 5% of hospice patients are under age 65), 27% had cancer as their principal diagnosis. The remainder suffered primarily from cardiac disease, dementia or any of a number of other conditions. Some of the non-cancer patients experienced pain, but many suffered chiefly from other symptoms such as nausea, confusion, or fatigue, most of which are not treated with opioids. 

Among hospice patients who do experience pain, hospice nurses, under the direction of a physician, arrange for medical treatment—and this commonly includes opioids. Opioids are also sometimes prescribed to ameliorate severe shortness of breath. This last claim sounds paradoxical—don’t opioids cause respiratory depression? In large doses or when rapidly escalating the dose they suppress respiration. Patients who are short of breath due to advanced heart or lung disease and whose underlying cause of the shortness of breath is no longer treatable often feel as though they are suffocating. They become tremendously anxious—which makes their breathing even worse. Low doses of opioids in this setting can make them less anxious, terminating this vicious cycle and providing a modicum of relief. 

Conventional wisdom in palliative care circles (palliative care is an interdisciplinary approach to advanced illness that encompasses but is not synonymous with hospice) is that with expert pain management, 90% of pain in serious illness can be well-controlled. This involves use of round the clock medication with supplementary doses for “breakthrough pain,” pain that develops before the next scheduled dose of medication. The medication is usually administered orally or via a patch on the skin; occasionally, a continuous intravenous infusion (“pump”) is needed and even more occasionally, a sophisticated method of providing pain relief will be provided by an anesthesiologist (for example, an epidural injection or a nerve block).

So perhaps quality of life can be improved in the hospice setting, but is it at the cost of shortening life?  What’s fascinating is that effective pain and other symptom management at the end of life may actually prolong life. This was demonstrated most dramatically in a widely cited study of patients with very advanced lung cancer. In this study, patients who got early palliative care alongside of traditional oncologic care had a median survival of 11.6 months compared to 8.9 months among controls who had usual care but did not receive palliative care. To put this in perspective, a differential survival of 1.7 months is substantial in the world of cancer. If a new chemotherapy drug resulted in an extra 1.7 months of life compared to conventional treatment, the new drug would get expedited approval by the FDA and be enthusiastically promoted by oncologists.

Maybe palliative care can prolong life, but palliative care does a great deal more than treat pain. Maybe the life prolongation that was found in the lung cancer patients is because their depression was treated or because they declined experimental chemotherapy that actually shortened life. What do we know about opioids themselves? Do they shorten life? This question is difficult to answer definitively because it’s not ethical to do a randomized study—taking two groups of people and assigning one group good pain management and another group inadequate pain management. We do know that among home care patients who received high or escalating doses of opioids, survival was the same as among similar home care patients who got low dose opioids. 

Perhaps opioids don’t shorten life on average, but you might think they precipitate death when used in actively dying patients. Once again, there are no good studies to address this question and there will never be any because we cannot ethically randomize dying patients to either receive doses of medicine that are adequate to relieve pain or to be left in pain. But after reviewing the available observational literature, physicians concluded that opioids prescribed in the palliative care setting for dying patients do not result in death. In fact, they argue that the “doctrine of double effect,” which is widely cited as justifying opioid-induced death by arguing the intent was pain-relief and not death, need rarely if ever be invoked.

Despite the data indicating that pain management near the end of life is tremendously beneficial and, in competent hands, is associated with minimal risk, pain in this setting continues to be under-treated. Contrary to the public perception that hospice nurses deliberately give high dose opioids to put patients out their misery, nurses tend to under-treat patients because they worry that opioids will cause harm. A recent position statement by the American Society for Pain Management Nursing and the Hospice and Palliative Nurses Association exhorts its members to “advocate for humane and dignified care, promoting ethical, effective pain and symptom management without exception.” This is not an endorsement of either physician assisted suicide (legal in 7 states and the District of Columbia under highly specific circumstances) or euthanasia (illegal throughout the US). Rather, it is a ringing endorsement of the view that high-quality pain management improves quality of life until the very end—and can decrease the demand for interventions of last resort like physician assisted suicide.

November 26, 2018

Robots to the Rescue?

Earlier this week, the New York Times featured an article entitled Meet Zora the Robot Caregiver. Zora, like her Japanese predecessors, the canine Aibo, the seal-like Paro, and the more recent humanoid Pepper, is being touted as a solution to manpower problems in geriatric caregiving. Can it work? And is it a good idea?

A friend who works in the robotics field reminded me of the potential of robotics when I wrote about the shortage of human caregivers to meet the needs of the coming wave of baby boomers entering old age. She acknowledged that today’s robots are limited in their abilities but is optimistic that when she and I may need their help—in 20 or 25 years—they may be ready. 

What exactly are robots being used for in the caregiving arena? Robots are being used for nursing home patients with dementia: they are used to calm people who are “antisocial, agitated, or sad” and asan antidote to loneliness. They provide reminders to forgetful elders to take their medications or go to the dining room for a meal. They show older people how to perform various exercises—repeatedly and with no sign of impatience. 

I have no doubt that robots are coming—this week also saw the publication of an essay in the New Yorker called Roomba Nation, which emphasizes the wide range of functions that robots can serve. Pepper, the previously alluded to  service worker in nursing homes, is also an employee of the hospitality industry. Paro (the robot seal robot) and Aibo (the robot dog) are purchased not only by nursing homes but also by facilities catering to disabled or depressed individuals. Robots clean floors in private homes and provide room service in hotels. And I have no doubt that robots can perform invaluable activities—minesweeping and disarming IEDs come to mind. 

But let’s be careful about just what tasks they replace and which functions they perform. Not that long ago, we began overhauling nursing homes so they would not serve merely as warehouses for older people, many of whom have cognitive impairment as well as physical disabilities. The practice of placing nursing home residents in wheelchairs, belting them in with restraints, and lining the chairs up in the hallway where nurses could “keep an eye on them” fell out of favor. It was replaced by an attempt (perhaps realized more often on paper than in reality, but an attempt nonetheless) to create a home-like environment where older people would feel valued and respected, and where they could find meaningful ways to spend their days. Critical to a sense of value, respect, and meaning are relationships. And relationships are between people. 

David Oliver, a geriatrician and general medical consultant in the UK, worries that the robotics industry may be driven in part by “marketing, the financial bottom line, and passive acceptance of workforce gaps.” Taking issue with the claim that robots can “provide rehabilitation…deliver personal care, and reduce social isolation,” he reminds us that “we should never forget that health and social care is a people business (emphasis added) and that those people might prefer more, not less, human contact.”

So—before we endorse the tagline, “robots to the rescue,” let’s think about the domains in which robots truly have something special to offer. In the nursing home setting, they could literally lighten the load for nursing aides, who right now have one of the highest rates of on-the-job injury in any industry, if they could lift patients out of bed and onto a wheelchair. That’s no easy task, both since we have to worry about the robot applying excessive force and crushing the person, and because frail, older people aren’t likely to remain motionless while they are lifted into the air. They could engage in monotonous, repetitive actions such as bringing lunch trays from the kitchen to their designated recipients. In the home setting, they may be able to provide 24/7 safety monitoring for older individuals with frailty or dementia, potentially allowing them to remain in their own homes with a spouse. But let’s make sure that the robots’ roles are to complement those of flesh and blood human beings. Let’s enable nursing aides and other caregivers to establish and maintain relationships with the subjects for whom they provide care. Let’s find ways to promote this newly reimagined career path to more people than are interested in today’s dead-end, low-paying, back-breaking jobs. Robots can help but they are not the solution.

November 19, 2018

Yearning to be Free

For the past couple of weeks, I have not found any burning geriatric issues to report on. So instead, I will discuss a burning moral issue, an issue that emerged 75 years ago--so perhaps in that sense it is a geriatric issue.            

            Nearly 76 years ago, on New Year’s Eve, 1942, three teenaged girls made their way through the snow and under a barbed wire fence from France to Switzerland. Cold, frightened, and desperate, they saw asylum in Switzerland as their only hope. They had been sent by their parents from their homes in Germany to Belgium to avoid persecution in 1939. When the Germans invaded Belgium in 1940, the girls had escaped to southern France where they lived in an abandoned castle with 100 other Jewish refugee children. They had been rounded up by the French police and would have been transported to Auschwitz if their supervisors from the Red Cross had not managed to intervene. They knew there would be another roundup and they would not be so lucky again. They knew that their days in France were numbered.
            The girls also knew that official Swiss policy was to turn away Jewish refugees who crossed the border. Despite the intelligence that had reached the Swiss government about mass murders of eastern Europe Jews, and despite the deportations of western European Jews that had begun earlier that year, the Swiss government sealed its borders in August, 1942.  While narrowly maintaining that it continued to provide asylum to “political refugees,” the government decreed that“refugees who have fled purely on racial grounds, e.g., Jews, cannot be considered political refugees. Such people should be refused entry without exception.” After widespread protests, the Swiss authorities allowed some exemptions, including pregnant women and children traveling alone under the age of 16. The three girls who walked across the border unaccompanied by adults that frigid New Year’s Eve were seventeen. One of them had turned 17 the previous week, on Christmas Day.
            They had no papers, so they lied about their ages—and they survived. If they hadn’t, I wouldn’t be telling this story, as one of those three girls would one day be my mother.  An estimated 24,500 would-be refugees were not so fortunate and were sent back over the Swiss border to face almost certain death.
            In the aftermath of World War II, the United Nations convened a conference on refugees. It was a direct response to the post-war refugee crisis in general and to the mistreatment of refugees by Switzerland in particular. At its heart is the concept of non-refoulement, a principle “so fundamental,” the Convention asserts, “that no reservations…may be made to it. It provides that no one shall expel or return (‘refouler’) a refugee against his or her will, in any manner whatsoever, to a territory wherehe or she fears threats to life or freedom.”
            The Convention was ratified by 145 countries in 1954. Broadened in 1967 to refer to refugees everywhere in the world, not just those seeking asylum during the 1940s, it was ratified by the United States and remains the basis of international law today. The Convention specifically stipulated that refugees should not be penalized for “illegal entry or stay.” 
            The refugees of today, including the group of desperate Central Americans proceeding on foot toward what they believe is their only chance of freedom, look a little different from those of the 1940s. They are women who have been threatened with rape if they fail to do the bidding of drug traffickers; they are adults who are lesbian or gay and are targeted for elimination by extralegal police; they are children whose relatives have been kidnapped for ransom and who fear a similar fate; they are men who have been extorted by organized crime. But, like my mother, her friends, and the other refugees from Nazism who were able to breach the Swiss border in the 1940s, the participants in the “Caravan” fear threats to life or freedom in the countries they come from. 
            We must not make the mistake of confusing “immigrants” with “refugees.” Immigrants are people from other parts of the world who seek a better life in this country. They want to come here to be educated, to work, and to live. The US sets its own policy toward these seekers and there is broad agreement that its current policy should be redesigned to better reflect our national interests. But refugee policy is set by international law. It is based on the enduring principle that anyone whose life or liberty is endangered in his home country and who manages to reach a freer country, however he manages to get there, is entitled to asylum. To violate that precept by failing to allow refugees to make their claims for asylum is to flout the internationally agreed upon principle of “non-refoulement.” It is to return to the barbarism of the past.

October 25, 2018

Frailty Matters

Last week’s British Medical Journal draws attention to the growing literature confirming that the intensive care unit (ICU) is a perilous environment for frail older people. A position piece written by an intensivist, a geriatrician, a professor of critical care, and a “patient and public representative,” argues there is a mismatch between the supply and demand for intensive care and that increased public awareness of what admission to the ICU does—and does not—mean for patients and their families is the key to addressing the problem.
Leaving aside whether the proposed solution, public education, has the slightest chance of working, I decided to have a look at the research papers on which the position piece was based. The first article, from Scotland and published in Critical Care Medicine, deals with “Health-Related Quality of Life After ICU.” The results, in a nutshell, are that what determined how well people did after discharge from the ICU in terms of both mental and physical functioning was affected far more by how well they functioned before they got sick than how sick they were when hospitalized.
The second article, based on patients in 311 ICUs in 21 European countries published in Intensive Care Medicine, found that among people over age 80, the greater the degree of frailty, the higher the 30-day mortality. In patients who, prior to admission, were not frail the 30-day survival was 76 percent; in the “pre-frail” group it was 71 percent, but in the frail group, it was 59 percent.
The importance of these studies is not so much the numbers they report—although I thought that a 30-day survival rate of 59 percent in frail octogenarians was not bad—as their emphasis on physical functioning. We in the U.S. continue to pay little attention to frailty. The Europeans, evidently, do pay attention to frailty. In part, the reason for the difference is that Europeans actually assess frailty while Americans, to a large extent, do not. We are still fighting over how best to measure and record it. The final takeaway from these articles is that the specific scale the Europeans use is so easy to use that the researchers did not have to teach physicians, patients, or families how to use it: it’s self-explanatory.

Forget about American exceptionalism. Let’s adopt the tool in use in the much of the rest of the developed world.

October 15, 2018

A Bone to Pick?

Increasingly, research studies published in major medical journals conclude the same way: with a plea for more studies. The writers say they have found evidence leading them to believe that drug X “may be helpful” or drug Y "did not produce a measurable difference in outcomes" and urge additional testing to confirm (or presumably refute) their results. So, it was interesting to note that a recent study of vitamin D and bone health concludes not only that the authors found no evidence that vitamin D is beneficial in preventing or treating falls, fractures, or osteoporosis, but that also that no further study is warranted. The writers confidently assert that this latest study, a meta-analysis that examines all the well-done studies to date, including 45 recent studies that were not included in previous meta-analyses, should be the last word on the subject. Unless you have rickets or osteomalacia, two relatively rare conditions, the authors conclude that you should not bother to take vitamin D supplements.
In the past, the response to negative studies of vitamin D has been a chorus of “but, but, but.” But what about the effect of the dose of vitamin D—maybe 400 International Units is not enough to do anything but 800 is. The current examination looked at this question and failed to detect any difference in outcomes between people taking high dose or lower dose vitamin D. But what about the importance of age—can vitamin D make a difference in the oldest old, people at the highest risk of fracture? The current examination didn’t find any evidence it does. But what about the thickness of the bones at the time that vitamin D is initiated—maybe it’s too late to matter if there has already been a great deal of bone loss, but can be helpful at an earlier stage. The authors of the new report don’t think so.
Two years ago, I addressed the issue of vitamin D in my blog post, “Make No Bones About It.” I concluded that the evidence supporting vitamin D supplements was weak, but because falls and fractures are so devastating for older people and the cost of vitamin D is so low, with almost non-existent side effects, it wouldn’t hurt to take it—and maybe, just maybe, it might help. What do I advocate today? What will I personally do? Well, I still have a large bottle of vitamin D (1000 IU capsules) in my medicine cabinet. I’ll finish the bottle. Then what? Unless someone comes up with a compelling reason to continue, I’ll probably stop. But I will make sure to drink lots of milk, eat cheese, and get plenty of sunshine to ensure that my non-medicinal intake of vitamin D is sufficient.

September 30, 2018

The Nurse Will See You Now


          Articles in medical journals tend to pay scant attention to the role of nurses in treating illness—or for that matter, to the role of social workers, physical therapists, and many other clinicians. Hence, when JAMA, one of the major American general medical journals, published an article in 2002 entitled, “Hospital Nurse Staffing and Patient Mortality, Nurse Burnout, and Job Dissatisfaction,” it was a bombshell. The lead author, Linda Aiken, is a nurse researcher at the University of Pennsylvania where she is a Professor of Sociology and the founding director of the Center for Health Outcomes and Policy Research. Looking at survey data from 10,000 nurses and administrative data on nearly 250,000 medical and surgical patients hospitalized in Pennsylvania in 1998-1999, she drew some dramatic conclusions: each additional patient per nurse was associated with a 7 percent increase in the likelihood of dying within 30 days of hospitalization, and each additional patient per nurse was associated with a 23 percent increase in the odds of “burnout” and a 15 percent increase in nursing job dissatisfaction. 

          Aiken's analysis, along with other smaller studies, have led to calls for an increase in the nurse to patient staffing ratios in hospitals. In light of general hospital administrative reluctance to make such increases, many nurses have demanded and some state legislatures have proposed mandatory increases in nurse to patient ratios. Massachusetts voters are being asked to vote this November on a referendum that would establish mandatory staffing ratios. To date, the only state to have instituted such a requirement is California—which passed legislation in 1999, before Aiken’s landmark study. California’s experience offers an unparalleled opportunity to ask whether mandatory ratios result in the desired improvements in quality of care and whether they produce a variety of unintended consequences. In principle, it could also shed light on whether nurse to patient ratios are particularly important for older people.

            California’s law specifies different nurse to patient ratios for intensive care units, surgical units, and medical units. Compliance was at first uneven, but gradually hospitals conformed to the requirements. Several studies have attempted to assess the outcomes. They are limited because California did not conduct a randomized, controlled experiment before passing its legislation—it did not impose mandatory minimum ratios on some hospitals and not on others. Moreover, nursing staff ratios are hardly the only factor affecting outcomes that changed in the early years of the mandate: many other federal quality improvement initiatives were undertaken to encourage hospitals to prevent pressure ulcers, falls, catheter-related infections and other major hazards of hospitalization. Hospitals have also experienced major financial pressures: the cost of hiring nurses was only one of many economic challenges. Determining cause and effect is not easy. Nearly twenty years later, what do we know?

            First and foremost, did the mandatory ratios result in improved quality of care? One of the most carefully performed studies was undertaken by the California Health Care Foundation, part of UCSF, in 2009. This report looked at pressure ulcers, pneumonia deaths, and deaths from sepsis (blood-borne infection) and were unable to find any statistically significant change after the law was implemented in 2004 (following a multi-year study period to design the regulations). Another study that focused exclusively on pressure ulcers and falls used data from CalNOC, a large nursing database for the entire state, to conclude there was no change in fall rates. They did note a paradoxical increase in pressure ulcers in patients admitted to “step-down” units, units between an ICU and a general medical or surgical floor in the acuity of their patients, after the requirement of more nurses per patient was introduced (presumably a reflection of sicker patients). A systematic review of the literature, published in the Annals of Internal Medicine in 2013, failed to find any statistically significant effect on a variety of safety measures. Of note, none of the studies I identified looked at either patient or nursing satisfaction.

            If mandatory nurse to patient ratios did result in more face-time with patients but no demonstrable improvement in overall quality of care, might older patients nonetheless be one subgroup that did benefit?  All we can say is that many of the quality measures that were examined—pressure ulcers and falls, for example—are particularly relevant to older people. 
            What about the feared adverse consequences of imposing rigid nursing staff ratios? An analysis in Health Affairs in 2011 found no evidence that hospitals were substituting less well-qualified staff (who still meet the legal requirements) such as LPNs for registered nurses. The California Health Care Foundation did conclude that hospitals were increasingly relying on “travel nurses,” (nurses from out of state or from other countries, hired for short periods of time) and on “float nurses” to move from floor to floor to compensate for lunch breaks by the regular staff. Such changes may result in less continuity of nursing care for patients. They also showed that hospitals across the state experienced shrinking operating margins beginning in 2002, especially in the hospitals that were initially fiscally strongest. However, they emphasize that many other factors could account for this phenomenon. Hospitals of all types did comply with the law, resulting in more hours of nursing care for each patient every day:
          On balance, regulating nurse to patient staff ratios in isolation is not likely to make much of a difference in patient outcomes, nor is it likely to devastate hospitals' finances. Hospitals are complex institutions with many interrelated parts. Just because hospitals with low nurse to patient staffing ratios tend to have poorer outcomes than other hospitals does not mean that if we "fix" the ratio, care will necessarily improve. Assuring that there are enough nurses to provide good care is essential, but that step alone is unlikely to dramatically improve the hospital experience.


September 24, 2018

Of Mice and Men

For middle-aged mice, these are the best of times. Scientists now understand genetic factors that lead to the development of disease, disability, and death—in mice. Most importantly, researchers have found ways to improve the “healthspan,” the period of disease- and disability-free life before death—in mice. The question is whether the approaches they are developing will be applicable to people, and the ethical implications if they are.
The basic ideas are spelled out in a trio of “viewpoint” articles published in JAMA last week. S. Jay Olshansky, writing from an epidemiologic perspective, observes that over the past century, dramatic gains in life expectancy have been accomplished by reducing in mortality of children and young adults. But once these gains have been made, the only remaining way to lengthen life expectancy is by extending the lives of people at the other end of the age spectrum. Medical science has therefore concentrated on tackling the diseases of old age, one by one. Unfortunately, as Barzilai et al comment in their essay, “efforts focused on preventing individual diseases will have limited net effect on population health because one disease will be exchanged for another.” We’re already seeing this phenomenon: as fewer people die of heart disease, they develop and die of Alzheimer’s instead. Far better would be to tackle the aging process itself. Targeting the underlying driver of all the chronic diseases at once could, in principle, prevent or at least delay those disorders.
So, what do we know about turning off biological aging? We know there’s a gene in mice with the euphonious name rps6kb1 and if it’s “knocked out” (molecular genetics speak for “inactivated”), female mice live longer, healthier lives. We know there’s another gene called Sirt6 (short for Sirtuin 6), which is present in multiple mammalian species including humans, and if it is “overexpressed” (genetics speak for “turned on”) in male mice, they live longer. We also know that all creatures including people have “senescent cells,” cells that, old cells that start releasing all kinds of chemicals. When an individual has more than some threshold number of such cells, it develops chronic diseases, frailty, and is at high risk of dying. When the senescent cells of a mouse are destroyed, the mouse lives longer and without a long period of deterioration before death.
And what progress has been made in identifying drugs that achieve these goals in mice? And what about in people? Reportedly, the Interventions Testing Program, funded by the National Institute on Aging, has examined 26 “candidate drugs” for their effects on mice. They have identified 6, including the anti-inflammatory drug, aspirin, the anti-diabetes drug, acarbose, the immunosuppressive drug, rapamycin, and the estrogen, 17a-estradiol, as effective in some mice. Intervening in mice of an age equivalent to 70 human years has “extended life by more than 20 years and increase[d] health span even more substantially.” Other studies have found that the drug dasatinib (related to the anti-cancer drug, Tarceva) has a powerful effect in destroying senescent cells. In mice that are the equivalent of 80 human years, treatment with dasatinib combined with quercetin (a plant chemical found in green tea, red wine, apples, and other foods) increases survival 36 percent without increasing disability before death.
We don’t know whether any of these chemicals work in humans. And we have no idea at all whether they will produce side effects, though we do know that earlier attempts to interfere with cell lifespan were associated with the development of cancer. This is not entirely surprising, as the essence of cancer is uncontrolled cell proliferation. So even the very upbeat article by Tchkonia and Kirkland, the third of the triad, ends on a cautionary note: “…Patients should be advised not to self-medicate with senolytic agents or other drugs that target fundamental aging processes in the expectation that conditions alleviated in mice will be alleviated in people.”
If, years from now, human studies indicate the drugs or others like them are effective, we will have to deal with the ethical implications of extending the “healthspan.” What will they cost? Will everyone have access to such medications? Will we create greater inequality within society? Between countries? Banning such research on the grounds that a ballooning of the elderly population is unsustainable is almost certainly going to be impossible—the lure of more disease-free life will be irresistible. But we can begin to think about the consequences of our brave new world.

September 17, 2018

An Aspirin a Day...

The headlines this week—aside from the hurricane, the typhoon, and the charge of sexual misconduct in the Supreme Court nominee—are all about aspirin. For older people, unless you live in the Carolinas or Hong Kong, this is definitely the story. A new study (reported as 3 separate studies but really just one study with three different endpoints) threatens to unseat aspirin from its coveted spot as the little-pill-that-could.
A single aspirin a day, many people believed, could stave off heart disease, stroke, cancer, and perhaps dementia. If taken as a “baby aspirin,” a dose of 81 mg a day instead of the 325 mg in a regular aspirin tablet, and with a special “enteric” coating to protect the lining of the stomach, it was touted as effective with virtually no side effects. The truth, unfortunately, seems to be that it is neither effective nor devoid of side effects when taken by healthy older people.
The study, published online in the New England Journal of Medicine, examines three plausible possible benefits of low dose, enteric-coated aspirin. First, they ask whether aspirin has a desirable effect on cardiovascular events such as heart failure requiring hospitalization, stroke, or heart attack. They found no difference in benefit between healthy older people in the US or Australia (where older was defined as over 70 except in blacks and Hispanics, where it was defined as over 65) who took 100 mg of aspirin and those who did not.
Next, they looked at whether aspirin has an effect on how long healthy older people live without developing a disability. Again, they found no statistically significant difference between those who took aspirin and those who didn’t.
Finally, they examined overall mortality in the aspirin-takers and the non-aspirin takers. Once again, the two groups were indistinguishable.
There was, however, one striking difference in outcomes between the 9525 people who were randomized to take aspirin and the 9589 people who were randomized to placebo: the risk of bleeding was significantly higher. And by bleeding, the investigators meant major bleeding such as a gastrointestinal bleed or an intracranial hemorrhage. 
Not only did this randomized controlled study fail to show any benefit from taking aspirin, and not only did it show an increased risk of harm, but even when the results were subjected to subgroup analysis, no group emerged as potential beneficiaries. The authors looked at the composite endpoint (dementia, death, or persistent disability) in several pre-specified subgroups. One was gender: in the past, aspirin has been touted as preventive for healthy men but not women; in this study, neither men nor women benefited. Another was frailty (though I’m not quite sure how 421 of the “healthy” elderly subjects could have met the definition of frailty): in this study, neither the frail nor the non-frail benefited. If anything, there was a trend towards worse outcomes in the frail group, though the numbers were so small that the difference was not statistically significant and might well be due to chance.
No study is perfect and this one is no exception. The median period of observation was 4.7 years, a relatively short period with respect to the time needed to develop dementia or heart disease. The analysis was done on an “intention to treat” basis, which is the way such studies are supposed to be analyzed, but in fact only 2/3 of the people assigned to take aspirin were actually taking it by the end of the study period. The benefit of aspirin might therefore have been under-estimated. The risk of bleeding, however, which was already substantial in the aspirin users, may have also been under-estimated. For some reason, the study used a 100 mg dose even though a standard baby aspirin contains only 81 mg: maybe the results would have been different with an even smaller dose. But the strengths of the study are impressive. It was randomized; follow up was almost complete; data collection seems to have been thorough and careful.
I have a confession to make: for several years, I took a baby aspirin every day. I’m under 70 and I’m female, so my physician did not recommend that I take aspirin. I took it nonetheless because I really don’t want to have a stroke and thought that just maybe taking aspirin was something I could do to help. I took it because years ago, before I went to medical school, I worked in a hematology research lab and spent my days studying platelet aggregation. It turned out that people who had taken a single aspirin tablet within two weeks of my testing their blood showed markedly decreased clumping of platelets, blood cells that are critically involved in the clotting process. About a year ago, I had several episodes of subconjunctival hemorrhage, a benign form of bleeding involving the blood vessels of the eye. I worried the bleeding might be related to aspirin, so I stopped taking it. 
Today, the evidence is compelling that for people without heart disease or dementia or stroke, an aspirin is more likely to cause harm than good. As of now, aspirin has joined the ranks of other failed panaceas such as estrogen and calcium supplements.