Trying to Make Sense of Puzzling Health-Care News

Musings from Doc Gumshoe: Aspirin, ADHD, CRISPR and more...

By Michael Jorrin, "Doc Gumshoe", December 19, 2018

Let’s lead off with a news item that Doc Gumshoe, despite his widely-acknowledged acumen, could not manage to figure out in the least.   It took an Op Ed in the N Y Times to sweep the cobwebs out of his noggin.   

The news item was this: children born in the month of August in a number of states in the US have the highest rates of attention deficit hyperactivity disorder, as compared with children born at other times of the year.   Specifically, children born in August were found to have a nearly 40% higher chance of being diagnosed and treated for ADHD than children born just one month later.   This was stated in the context of a general report on the diagnosis and prevalence of ADHD, which included such puzzling bits of data as that three times as many children in Kentucky receive that diagnosis as do children in Nevada.   One in five children in Kentucky is diagnosed with ADHD, and about 5% of all children in the US currently are taking some form of medication for ADHD.  

My initial response to this was that it had to be a diagnosis issue, and not a matter of the prevalence of the actual condition.   I could not imagine that what sign of the Zodiac kids were born under could have any effect on their ADHD, although perhaps there could be a difference based on the time of year in which the mother brought the infant to term.   Was it possible that kids brought to term in the hot summer months might have different developmental characteristics than those who rested in their mothers’ wombs until the cozy winter months?

The puzzle was more or less cleared up by the aforementioned Op Ed, which in turn referred to a paper in the New England Journal of Medicine.   (Layton TJ N Engl J Med. 2018 Nov 29;379(22):2122-2130)  The underlying reason for the peculiar prevalence of the ADHD diagnosis in August-born children is almost certainly that in 18 states, in order for a child to be enrolled in kindergarten for the school year, a child has to reach his or her fifth birthday before September 1st.   So if the birthday of the kid in question is August 30th, he/she gets into kindergarten right away, but if it’s September 1st or after, he/she has to “wait ‘til next year.”  The result of this rule is that the kids born in August are the youngest in the class.   And, as a result of being the youngest, they also act the youngest – a bit more inattentive and fidgety.   A few months make a lot of difference in the development of a young child.   Parents are well aware of this; however, teachers – who were largely responsible for labeling these kids as being affected by ADHD – are more likely to have equal expectations for all the younglings in their classroom and tag the younger ones with ADHD when they’re really only acting their age.

All of this needs to be considered in the context of what many experts consider to be the significant overdiagnosis of ADHD, which has serious potential consequences when there are attempts to treat the condition through drugs.   ADHD drugs need to be considered with great care before prescribing them for children, especially very young children, who might well continue using these drugs for long periods.   A misdiagnosis, based on an age difference between a kid and his peers, could have enormous consequences.           

The aspirin paradox: which way to jump?

I preface this discussion by stating that I take a daily full-dose (325 mg) aspirin.   I’ve been doing it for about 30 years, and I’m not going to quit.   But the contradictory news items are nonetheless of concern.

Most recent was the report of the ASPREE trial, conducted in Australia and the US.   (McNeill JJ N Engl J Med. 2018 Oct 18;379(16):1519-1528).   This was a placebo-controlled trial, comparing 100 mg enteric-coated aspiring with placebo in 19,114 healthy older individuals, mean age 74 years, for a period of five years.   The short take is that daily low-dose aspirin did not result in any benefit in terms of the primary combined endpoint, which was death, dementia, and persistent physical disability.   The event rate in the placebo cohort was a tiny bit lower than in the group taking the daily aspirin – 21.2 events per 1,000 person-years in the placebo group versus 21.5 per 1,000 person-years in the aspirin group.   

Particularly attention-getting in this trial was the reported failure of aspirin to bring about a significant reduction in the risk of cardiovascular disease.   The aspirin treated cohort experienced 10.7 cardiovascular events per 1,000 person-years, while the placebo group experienced 11.3 events per 1,000 person years, a non-significant difference.

As expected, major hemorrhages and gastrointestinal bleeding were occurred with somewhat more frequency among the aspirin-treated group than among those subjects taking the placebo.

In contrast, a large cohort study in Sweden found that stopping low-dose aspirin led to a rapid and significant increase in the risk of heart attacks and strokes.   (Sundström J.   Circulation. 2017 Sep 26;136(13):1183-1192).     The study followed 601,527 Swedish adults, age 40 years or more, who were prescribed low-dose aspirin, for a period of three years.   In Sweden, we note, aspirin is given by prescription and not over-the-counter as in the US.   At the start of the study, all study participants were taking aspirin, but during the three-year course of the study about 15% of the participants stopped taking aspirin.   

Overall, 62,690 heart attacks, strokes, or deaths from cardiovascular causes took place in the persons followed by the study.   The rate of these events was 37% higher in the subjects who discontinued aspirin than in those who stayed with the treatment plan.   This corresponded to one additional cardiovascular event observed per year in one of every 74 patients who quit taking aspirin.   The study authors note that the risk increased shortly after discontinuation of aspirin and did not appear to diminish over time.   In the group of patients who had already sustained a cardiovascular event and had been prescribed aspirin in the hopes of avoiding a repeated incident, there was one additional signal cardiovascular event for every 36 patients who dropped their aspirin regimen.

A spokesperson for the American Heart Association, Dr Nieca Goldberg, agreed, commenting that “once you stop aspirin, the blood’s clotting tendency goes up.”   And, as we know, blood clots are a principal cause of strokes and are also involved in myocardial infarctions.   

What might account for the difference in the results of these two studies?   In the Australia/US study, daily aspirin delivered no benefit, while in the Swedish study, individuals who stopped taking aspirin quickly experienced a significant uptick in the rate of serious cardiovascular events, strongly supporting the conclusion that aspirin did result in cardiovascular benefit.   How can that be?

If we look at the patient populations in those two studies, clear differences emerge, and these differences probably account for the differences in the study outcomes.   The Australia/US study was a prospective placebo-controlled study in older patients who were in good health at the start of the study.   It was specifically focused on the question whether daily aspirin was effective in primary prevention – that is, in prevention of the primary occurrence of disease.   The Swedish study was observational, in a much larger group of much younger patients.   We don’t know anything about the health status of the patients in the Swedish study, but we do know that they were prescribed aspirin.   It’s highly likely that in many of those patients aspirin was intended for secondary prevention, meaning that many patients had either already experienced a stroke or myocardial infarction or were at elevated risk for some kind of cardiovascular event.   

And while we’re on the subject of aspirin, two studies were recently published in JAMA Oncology.   (Barnard ME.   JAMA Oncol. 2018 Oct doi: 10.1001/jamaoncol.2018.4149; Simon TG.    JAMA Oncol. 2018 Oct doi: 10.1001/jamaoncol.2018.4154.).  Both were based on analysis of follow-up data from the Nurses’ Health Studies, which ran from 1980 to 2015.   One study found that women who regularly took low-dose aspirin had a 23% reduction in ovarian cancer as compared with aspirin non-users.   The other study reported a 49% reduction in the incidence of cancer of the liver in women who took regular (not low-dose) aspirin twice-we