Richard Lehman’s journal review—16 July 2018

Richard Lehman reviews the latest research in the top medical journals

NEJM  12 Jul 2018

TAILORing fails to provide a better fit

Some people find it fun to add to the chaos and anxiety of the world, while others don’t find it fun, but still end up doing it. We really need a scale to measure this, and every child should be taught to plan their life to achieve a score of minus 100 Trumps. I’m not sure where cancer response prediction tools fall on the Trump scale, because I can’t work out if those who devise them are simply out to make money, or genuinely believe that they will help to allocate treatment. By ill chance, I spent several months thinking about this in relation to a 21-gene “panel” test for predicting response to drug regimens for breast cancer. We looked hard at the evidence and concluded that there was insufficient evidence about the predictive value of the panel test when it put patients in an “intermediate” category of risk. Now here comes the result for the TAILORx test in a prospective cohort of patients in this class.

Intermediate values are quite valueless in predicting a between a good response to adjuvant endocrine therapy versus chemoendocrine therapy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer. Fortunately, both groups do very well whichever treatment they get.

A different approach to breast cancer “tailoring”

Premenopausal women were randomly assigned to receive five years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.” Wait. This is already too much for the average reader to take in.

In fact this is a follow-up study of two trials using four different kinds of ovarian suppression, and a broad, 20-year old definition of breast cancer. Being part-funded by Pfizer, the manufacturer of exemestane, it might be expected to come out in favour of exemestane. But no: there was no meaningful difference between groups: “The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression.” That’s what it says in the results section. But most readers will default to the conclusions section, which says, “Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence.” Note that the puff for exemestane is achieved by a sudden change in outcome measure to progression free survival rather than overall survival. The latter was actually slightly worse when ovarian ablation was combined with exemestane rather than tamoxifen. 

TB vaccination 100 years after BCG

It is roughly 100 years since two French bacteriologists developed bacille Calmette–Guérin (BCG) vaccine as a protection against human tuberculosis. It is very difficult to make sense of the century’s worth of data about its protective efficacy, but nobody would disagree that a better replacement is overdue. Yet testing TB vaccines is so difficult: in high prevalence areas most babies get BCG at birth, and distinguishing between latent and active TB is still an imperfect science. Here’s a phase 2 study of a candidate vaccine called H4:IC31, compared with BCG revaccination. The conclusion is comprehensively tentative: “In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates.” QFT stands for QuantiFERON-TB Gold In-tube assay.

JAMA 10 Jul 2018

Detecting more AF: a self-evident good?

A major goal of detecting more atrial fibrillation is, of course, to prevent more strokes. Like most doctors, I really don’t want to have a stroke. I’ve had brief glimpses of what it might be like to be unable to find words, during severe focal migraines, and being stuck like that forever seems to me worse than dying comfortably by exsanguination, of which I’ve also had a slight foretaste. So I’d go for anticoagulation if I had AF and no contra-indications. Now there’s been a lot of recent debate about screening for AF as “opposed to” case-finding, though most people can’t tell you how the two differ. In this study, they went all-out to detect AF by means of a self-applied patch which recorded an ECG over two weeks in high-risk adults. High-risk was defined by age and/or comorbidities such as sleep apnoea, high blood pressure, mitral valve disease etc.  

The most relevant figure is probably the one-year detection rate of AF, which was 4% higher in absolute terms in the continuously monitored group as opposed to those who had a resting ECG four months later. And that’s about it for now: to know their outcomes in real terms, we’ll have to wait five years or more. Oh, and having started with stroke, I should mention that the commonest unwelcome effect of AF is actually heart failure.

JAMA Int Med July 2018

BP: the encouragement paradox

In this cluster randomized clinical trial of 794 patients with hypertension, electronic health record tools designed to support medication self-management improved medication reconciliation, but may have worsened blood pressure. Electronic health record tools combined with nurse-led medication education were associated with lower blood pressure compared with electronic health record tools alone, but had no effect on medication adherence or drug indication knowledge.” I think I’ll leave it there: it’s a great demonstration of the principle that the only way to find out whether an idea works for humans is to test it in humans. “From the crooked timber of humanity, no straight thing was ever made.” I. Kant.

Amputation in dialysis patients often presages death

Here’s a study looking at 3.7 million Americans with end-stage renal disease, picking out the ones on dialysis who went on to have lower limb amputation. Not surprisingly, half of them had diabetes and half of them were dead within a year of amputation. Not a cheerful article then, but there was another half in the equation: the number of people on dialysis needing lower limb removal halved between 2000 and 2014. We—or at least the Americans—must be doing something better.

The Lancet 14 Jul 2018

The Meaning of Montgomery

The case of Montgomery v Lanarkshire Health Board 2015 is much discussed at the sort of meetings I find myself attending these days. People who ask me if I wouldn’t rather be playing golf at my age tend to get a short answer, the second part of which is “off”. I’d rather be part of a social movement for the shared understanding of medicine, and the Montgomery ruling is an important driver for this—especially among surgeons, who are now ahead of most physician colleagues in dropping their traditional paternalism. The High Court ruling established the principle that doctors must ensure patients are aware of any material risks involved in a proposed treatment, and of reasonable alternatives. The wording of the ruling was very moderate, but shifted the focus decisively away from the Bolam principle, based on what a reasonable doctor might do, towards the individual patient and their informed viewpoint, which now are the standard by which consent is measured. If you can spare time from golf, I would recommend this lucid summary, which contains some intriguing suggestions such as “In general, developing innovative digital ways of obtaining and recording informed consent would help to bring the UK’s National Health Service closer to achieving its goal of shared decision making.”

Monkeying with HIV vaccine

Oh look, Janssen may have an HIV vaccine in the pipeline. “The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa.” That’s it folks. Worth a couple of sentences in a trade journal at this point, perhaps. But a full paper in The Lancet?   

Weighing the effects of aspirin

But now for something truly mighty. The debate about the right dose of aspirin for primary prevention started in the 1980s, when I remember a cardiology professor saying “if you just keep an aspirin tablet on the bathroom shelf and lick it every day, you’ll probably be about right”. Back then there was something called “children’s aspirin” which was fixed at a dose of 75mg in the UK and 82.5mg in the USA. When aspirin was found to kill children through Reye’s syndrome, these doses persisted as the standard doses for cardiovascular protection. Enter Peter Rothwell and his team with a magnificent individual participant data analysis of the preventive effect of aspirin 75-100mg according to body weight and other individual characteristics. “Low doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin’s effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required.” Note that this has only been demonstrated for primary prevention so far. But it has enormous repercussions for all preventive uses of aspirin. When Bayer first made its fortune by selling acetylsalicylic acid as an analgesic in 1899, little could anyone have foreseen that dose-finding studies for the prevention of stroke, heart attacks and cancer would still be going on well into the twenty-first century.  

The BMJ 14 Jul 2018

Gestational dimeric inhibin-A and later CVD

Another cardiovascular risk factor! Doesn’t your heart leap! And actually there are stacks more if you look at the blood tests done on every pregnant Ontarian woman from 1993 onwards: “Women with abnormal prenatal biochemical screening results, especially for dimeric inhibin-A, may be at higher risk of cardiovascular disease. If these findings are replicated elsewhere, a massive amount of data exists that could aid in identifying women at higher risk of premature cardiovascular disease and that could be conveyed to them or their healthcare providers.” Um, yes. And the marginal value of this would be…?

Let hypertension abound

I’ve spoken before about the American College of Cardiology/American Heart Association guidelines on hypertension, and in this article Harlan Krumholz and colleagues from China flesh out the original estimates of how this relabelling exercise might affect people. “If adopted, the 2017 ACC/AHA hypertension guidelines will markedly increase the number of people labeled as having hypertension and treated with drugs in both the US and China, leading to more than half of those aged 45-75 years in both countries being considered hypertensive.” In truth, the proponents of the Polypill 25 years ago were absolutely right in their logic from a population point of view. Everybody in the herd should knuckle down and take their medicine. It is only from the individual’s point of view that we are reaching the point of absurdity, and the greatest value of this paper is to identify the issues which need to be sorted out in order to make informed individual choices about blood pressure medication.  

Plant of the Week:Tilia tomentosa “Petiolaris”

Size is not everything in the world of plants, but if it were, then the weeping silver lime tree might rank as the greatest flowering plant of the temperate north. It can grow massive, up to 40m high, and has a natural shapeliness of curve going right down to the ground. Its leaves are of a noble dark green, but with flashes of silver underside when caught in a summer breeze. It probably carries more flowers than any other tree of its size, and although they are not showy in themselves, their scent fills whole streets at this time of year.

To call them intoxicating is just to state a simple fact, attested by hundreds of drunken bees which crawl around the sticky flowers on the ground beneath. For this reason these magnificent trees should be planted well back from any town pavement, and one would be well advised not to lie beneath one in high summer. It is best simply to breathe the scent from a safe distance, like the summer lover in Mahler’s Rückert song, Ich atmet’ eine linden Duft, rather than the wanderer in Schubert’s Winterreise who lay beneath der Lindenbaum and now, in the depths of winter, can never find rest again.