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. 

The Secret to Staying Sharp

The last time that NIH requested a review of the data on preventing cognitive decline in old age (including Mild Cognitive Impairment, Alzheimer’s type dementia, and “usual” age-related cognitive deterioration) was in 2010. At that time, the systematic review of the published literature (performed by the Agency for Healthcare Research and Quality) and the associated state of the science conference (convened by NIH) concluded there was insufficient evidence to make any recommendations about interventions to prevent cognitive decline and dementia.

Now, the NIA has asked the National Academies of Science, Engineering, and Medicine to commission a new systematic review of the data and, based on that review, to issue recommendations about prevention. Its report, optimistically entitled, “Preventing Cognitive Decline and Dementia: A Way Forward,” was just released.  Alas, while the commission bent over backwards to find beneficial interventions, adding observational, non-experimental studies, risk factor analysis, and neurobiological work to the randomized controlled trials (RCTs) that were supposed to provide the evidence for their conclusions, it was forced to conclude, once again, that  the review “identified no specific interventions that are supported by sufficient evidence to justify mounting out an assertive public health campaign to encourage people to adopt them for the purpose of preventing cognitive decline and dementia.” The best the group could come up with was that the review did “find some degree of support for the benefit of three classes of intervention: cognitive training, blood pressure management in people with hypertension, and increased physical activity.

If we examine these three domains, what we find is not entirely encouraging. The arena of cognitive training (brain games, crossword puzzles, studying a foreign language, etc.) had the greatest degree of evidence. There is good evidence that it can improve performance in a trained task—that is, if you work at generating synonyms for words over and over again, you will get better at finding synonyms, at least in the short term. What is less clear is whether the benefits are sustained, whether training in one domain yields benefits in other domains, and whether it translates at all into improvement in daily functioning, in areas such as shopping, cooking, or paying bills. The good news, such as it is, about cognitive training, derives principally from one study, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE), which provides moderately strong evidence of effectiveness in the training domain after 2 years but low strength evidence after 5 or 10 years. The improvements that were found failed to translate into areas other than the one where training was provided.

Perhaps surprisingly, given the strong evidence that blood pressure control in people with hypertension is beneficial in preventing stroke and coronary artery disease, vigorous blood pressure treatment did not so readily translate into prevention or delay of any form of cognitive decline in old age. One British study did show efficacy. Given that blood pressure treatment is already recommended for other reasons, encouraging its use in the hope that it might also help fend off cognitive decline evidently seemed harmless enough to the committee.

The story on exercise is similar to that on blood pressure control: the RCT data are inconsistent, but there’s at least some data that shows a positive effect. Exercise studies are problematic because they so often utilize different forms of exercise and prescribe varying duration and frequency of exercise. Nonetheless, given the evidence that exercise is useful to promote mobility and to prevent depression, and that some studies find it beneficial in preventing cognitive decline, the committee opted to include exercise in its short list of interventions for which there is “some degree of support.”

The main justification, it seems to me, for subtitling this report “A Way Forward” is the section on recommendations for future research. The areas that have shown some promise deserve further study. And that study, as well as all other avenues that might be pursued, should be methodologically sound. That means acknowledging the deficiencies of existing work and avoiding those flaws in the future.

I suppose that whether this report is encouraging or not depends on whether you are a glass half full or half empty sort of a person. I will certainly continue to exercise regularly and challenge my mind, as long as I am able to. If I develop high blood pressure, I’ll want it adequately controlled. But I won’t kid myself that any of these measures will get me off the hook. And I will continue to support ongoing research in preventing or delaying cognitive decline in old age. But I won’t hold my breath. So far, the secret to staying sharp is that there isn't one.

An Ounce of Prevention

Kaiser Health News, one of the best sources of reporting about issues affecting older people, ran a story last week about the re-emergence of “death panel” agitation. Most of us thought this non-issue was dead, but apparently Representative Steve King of Iowa has decided that the decision by CMS to reimburse physicians for advance care planning discussions should be euthanized by Congress. Accordingly, he has introduced a bill called “Protecting Life Until Natural Death” with the explicit goal of instructing CMS to stop paying for conversations about the end of life. Which is too bad, since CMS just reported than in the first six months of 2016 alone, close to 14,000 clinicians billed for such discussions for 223,000 patients.

The irony is that the very idea of discussions by patients and their families about how they wish the end of life to unfold was spurred by a concern that patients aren’t being allowed to die a “natural death.” Instead, they have been forced to endure a technological death, death on a ventilator, in an ICU, while iatrogenesis-inducing medication is pumped in. In fact, as Representative King may or may not be aware, some physicians and ethicists advocate substituting the phrase “allow natural death” for the still oft-misinterpreted “do not resuscitate.”

There’s another reason that the proposed legislation is misguided. While advance care planning conversations are often advocated as a means of avoiding unwanted medical intervention near the end of life, they are better characterized as preventive medicine. Enabling people to talk about what matters to them and how they wish to be treated if they are very ill, approaching the end of life, and unable to speak for themselves, has the potential to ensure that patients are neither over-treated nor under-treated. It gives them the opportunity to state clearly and unambiguously that they would want to be put on a ventilator if they develop respiratory failure in the setting of advanced emphysema, however small the likelihood that they will be able to be weaned from the machine. It gives them the chance to say explicitly that they would want to be maintained with a feeding tube if they are in a persistent vegetative state, even if there is no chance of ever emerging from that condition.

What advance care planning does is to enhance patient choice. It doesn’t give government –or physicians, or health care surrogates, or families—the right to decide what treatment a patient will receive when he or she is dying. It assures that patients will make their own decisions about what kind and how much medical treatment they want. Surely that’s what Representative King wants for himself.

Luck and Genes

My mother’s friend Lixie died last month. Eight months ago, her husband (my father) died. And just about exactly a year ago, my mother’s friend Walter died.

The three of them were all in their 90’s: Lixie died 6 weeks after turning 92; my father also died 6 weeks after turning 92; Walter died 6 weeks before he would have been 92. My mother, who still lives independently though she is not as vigorous as she was a few years ago, reached age 91 in December.

They had something else in common: all three were born in Germany or Austria in the 1920s and left thanks to the efforts of a group of Belgian Jewish women who sought to rescue Jewish children from an uncertain fate. The group of 93 children stayed in Brussels until the Germans invaded Belgium. They then made their way to unoccupied France, where they found refuge until 1942, when France no longer provided a safe haven for them. My parents escaped individually to Switzerland and eventually, well after the end of the war, made their way to the US. Lixie remained in hiding in France until the end of the war. Walter was one of the few teenagers to manage to immigrate to the US during the war. The story of the “Children of La Hille” is told by Walter in a book published shortly before his death; I tell parts of the story in my memoir about my parents, Once They Had a Country. 

Of the 93 children in the original group that made their way to Brussels, 82 survived the war.  And of those 82, many are living into their nineties. In addition to the four I mentioned above—my mother and the three who died within the past year—I know of another three who are alive and over ninety. There may be more. Surely this is more than one would expect in a cohort of people born in Europe in the mid-1920s.

Curious, I looked at what is known about the longevity of Jews who survived the trauma of 1939-1945 in Europe. And what I found was very interesting indeed. An article called Against All Odds found that survivors of “genocidal trauma” during World War II were likely to live longer than a comparable group not exposed to the same trauma.

The study looked at Israelis born in Poland who were between 4 and 20 years of age in 1939. They compared those who came to Israel before 1939 with those who arrived between 1945 and 1950, defining as "Holocaust survivors" anyone who spent the war years in Europe, regardless of whether they were in a concentration camp, hiding in a convent, or on the run. The justification for this broad definition is that in all cases, their lives were in extreme jeopardy. 

The authors of the study examined at the experience of 41,454 Holocaust survivors and 13,766 controls. What they found was that Holocaust survivors were on average likely to live 6.5 months longer than those who were not in Europe during World War II. This despite ample prior evidence that Jews who spent some or all of the war years in Europe had a high rate of post-traumatic stress disorder in later life.

What does this mean? It’s not certain what it means, but one possibility is that whatever factors led this high risk group to survive under adversity also led them to survive into old age. And since there’s no reason to believe that just because you were lucky once, you’ll be lucky again, I suspect that a key factor is genes. Those Jewish children who managed to survive the war, including the Children of La Hille (who, because of the assistance they received, faced better odds than their counterparts who were not part of this group), were better equipped to endure. That capacity continued to help them for the remainder of their lives.

This explanation is, of course, entirely speculative. It’s conceivable that the longevity of the Children of La Hille is simply due to chance. But I am telling this story because it is a reminder that much of the experience of aging is shaped to a large extent by factors beyond our control—by luck and genes. 

This doesn’t mean we shouldn’t try to improve our chances of survival by preventing whatever part of illness and disability is preventable. It doesn’t mean we shouldn’t do what we can by exercising and eating a good diet, by avoiding drugs and alcohol, and by controlling conditions such as high blood pressure. But let’s have the humility to remember that we have only a modest ability to determine our fate. All those who, unlike the Children of La Hille, don't have good luck and good genes, should nonetheless have access to the medical care, housing, and social services that allow them to have as good a quality of life as possible, however many years they live.

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