Richard Lehman’s journal review—21 March 2016

richard_lehmanNEJM 17 Mar 2016 Vol 374
Unnecessary pessary
1044 “This randomized trial showed that placement of a pessary in girls and women who were pregnant with singletons and who had a short cervix at 20 to 24 weeks of gestation did not result in a lower rate of preterm delivery before 34 weeks of gestation than the rate with expectant management.” The last sentence of this paper tells you all you need to know, leaving me free to muse on the rhyming possibilities of the word “pessary”. I think I have already exhausted them in the title. But this does remind me of the quatrain written by a nineteenth century bishop when challenged to come up with rhymes for “cassowary” and “Timbuctoo”:
If I were a cassowary
On the plains of Timbuctoo
I would eat a missionary,
Cassock, bands, and hymn-book too.
This has been variously misquoted and misattributed, but it was most likely written by Samuel Wilberforce, Bishop of Oxford from 1845 to 1869, who became famous for mocking Darwin’s new Theory of Evolution at a public meeting and being coolly demolished by Thomas Huxley. He was known as “Soapy Sam” and he once led a procession of 100 vested clergy through the streets of my local town, Banbury, in the hope of attracting them to the Church of England. It is nice to have this further proof of his sense of humour.

Safer prescribing in Tayside
1053 Oh dear, only item two and this is threatening to become a Bad Poetry issue. The reason is that the next study is from Tayside, a location which always brings out my inner William McGonagall. Let’s get the poetry out of the way first:
The folk by the silvery Tay were taking too many medicines,
Causing them to bleed and have trouble with their intestines;
So their doctors were subjected to cluster randomization
To test the effect of bribes and figures and better education.
And so all the way from Perth to Carnoustie
The health of the people received a wee boostie.
But ’tis a question of future debate most bonny
If ’twas due to the instruction or the effect of the money.
In case you haven’t got the gist, here’s the prose version: “In this cluster-randomized, stepped-wedge trial conducted in Tayside, Scotland, we randomly assigned participating primary care practices to various start dates for a 48-week intervention comprising professional education, informatics to facilitate review, and financial incentives for practices to review patients’ charts to assess appropriateness. The primary outcome was patient-level exposure to any of nine measures of high-risk prescribing of nonsteroidal anti-inflammatory drugs (NSAIDs) or selected antiplatelet agents (e.g. NSAID prescription in a patient with chronic kidney disease or coprescription of an NSAID and an oral anticoagulant without gastroprotection).” Note that it was the start date which was randomized, not the intervention itself. So the comparisons are before-and-after, not between-group. The prescription of the target drugs to high-risk patients certainly diminished and there were fewer admissions for GI ulcers, bleeding and heart failure in practices after the intervention.

Asthma: trials and deceptions
OL When giving people long-term treatment, it is best not to kill them. Primum non occidere. Especially when they may be mislabelled and/or the treatment may not be doing anything anyway. And so we come to the vexed question of which people with the label “asthma” might be helped or harmed by inhaling long-term adrenergic agonists, with or without corticosteroids. This GSK-funded trial chose to pose the question the other way round: does adding salmeterol to fluticasone in a fixed-dose inhaler pose any greater hazard than using fluticasone alone? On the face of it, this trial seems OK: “Eligible patients had at least a one year history of asthma, required daily medications for asthma control, and had received treatment with systemic glucocorticoids for an asthma exacerbation or had been hospitalized for an asthma exacerbation during the previous 12 months, with the exclusion of the 30 days before randomization.” And salmeterol seemed to help, reducing exacerbations by 25% (much less in absolute terms) in the 11, 679 participants, and not increasing the risk of serious asthma-related events, a composite end point that included death, endotracheal intubation, and hospitalization. But as the excellent accompanying editorial points out, there is a snag. “Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. Why this decision was made is never explained, but it is bewildering that the patients at highest risk for the composite primary outcome were purposely left out. It has been shown, for example, that almost two thirds of patients who were hospitalized with life-threatening asthma had a history of admission to an intensive care unit, as compared with only 11% of patients who were admitted with severe but not life-threatening asthma. Thus, it is not surprising that only two patients in the trial had life-threatening asthma and that adherence to study medication was 95%, a rate of success unheard of in clinical practice and even in highly controlled clinical trials.” If anyone doubts that clinical trials should cease to be designed or conducted by the manufacturers of the product, here is the proof.

Ann Intern Med Mar 2016 Vol 164
Genes on the screen
OL Here’s an online survey of people in the USA who had undergone commercial direct-to-consumer genetic testing. Among 1026 respondents, 63% planned to share their results with a primary health provider. But at six months, 27% reported having done so, and 8% reported sharing with another health care provider only. So although direct-to-consumer gene testing has the capacity to overwhelm health systems, human inertia is coming to the rescue. Common reasons for not sharing results with a health care provider were that the results were not important enough (40%) or that the participant did not have time to do so (37%). And what happened when people did go and see their primary care physician with the print-out? “35% were very satisfied with the encounter, and 18% were not at all satisfied. Frequently identified themes in participant descriptions of these encounters were actionability of the results or use in care (32%), PCP engagement or interest (25%), and lack of PCP engagement or interest (22%).” I think that’s an amazing rate of satisfaction. American doctors must understand a lot more about the meaning of these tests than I do.

Stop it at once
OL Slightly more people manage to stay off cigarettes if they give up abruptly than if they reduce gradually. This is the much reported study of 697 smokers in English primary care centres, in which both groups received behavioural support from nurses and used nicotine replacement before and after quit day. The overall difference at six months was 6.5% of the sample. So when you say to a patient “You’re more likely to be successful if you stop altogether than if you try to cut down over two weeks”, that’s just about true.

JAMA 15 Mar 2016 Vol 315
The Life of P
1141 In his essay “Evidence-based medicine has been hijacked: a report to David Sackett” John Ioannidis has bared his soul and detailed a long and often seemingly futile quest to address the distortion of medical research and reporting. In this paper, he and his team get down to looking at the reporting of P values in the medical literature between 1990 and 2015. Like most statistical terms, P values are best understood as an aid to gambling. If you are gambling over nothing, then the odds hardly matter. If you can have 60 goes at something, then odds of 1 in 20 become attractive. And so on. The authors find that in medical articles, P values have become commoner and commoner, but are rarely given unless they are “significant” at the 0.05 (1 in 20) level, and few articles included confidence intervals, Bayes factors, or effect sizes. The full article may be for anoraks only, but here is the message succinctly put by Philip B Stark of the University of California at Berkeley:

“The problem with P values is a problem shared by most if not all statistical techniques: it needs to be used intelligently and carefully. One of the biggest pitfalls of using P values is to ignore the process of selecting which hypotheses to test and which inferences to report. Virtually every statistical test for quantifying uncertainty has the same vulnerability.”

Xenon & the brain
1120 Xenon is a noble gas. Not just my opinion, ask any chemist. Xenon is a strange thing. Again, not my opinion, ask any ancient Greek (xenon means strange [neuter]). Xenophobia is rife in medicine, in the sense that I’ve never come across this strange noble gas in a longish clinical career. But in this trial they gave inhaled xenon to comatose survivors of cardiac arrest to discover if it reduced brain damage. On the MRI scans at 6 months they could detect some differences, but in terms of mortality or neurological function, there was none. They call for further research, but I think this is taking xenophilia too far.

Lancet 19 Mar 2016 Vol 387
1163 The STAMPEDE trial appeared on the Lancet website in Christmas week, but despite the title I wasn’t in a hurry to talk about it. It reports the “primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone” in men with advanced prostate cancer. I won’t try and go into detail, though this a very important issue for an increasing number of men facing ultimate death from this cancer. Here’s the conclusion: “Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.” Yes, sort of. What such men need is not so much “standard of care” as a well-crafted visual decision aid to fit their treatments with their preferences over a median survival period of 71 months.

1187 I just think everyone should know about this word and practise saying it aloud. Lipoarabinomannan is a glycolipid antigen of the M tuberculosis cell wall. It can be detected in a tiny amount of urine from patients whose TB may be masked by other illnesses, especially HIV. Lipoarabinomannan. Yes.

BMJ 19 Mar 2016 Vol 352
We’ve got inertia in our DNA
Gather round, dear children, and hearken to the wisdom of an old man. Throughout your life you will gather knowledge. And often, I hope, you will share your knowledge with others. But then you will learn a hard lesson. Oft-times these others would rather not have your knowledge. And if they listen, they may not learn. And if they learn, they may not change. Knowledge in itself achieves nothing unless people are willing to change. Now I must fold my hands and sleep.

These senile bumblings are inspired by a systematic review of the impact of communicating DNA based disease risk estimates on risk-reducing health behaviours and motivation to engage in such behaviours. It meshes perfectly with the study I mentioned from the Annals website. If you have your DNA scrutinized by some “state-of-the art” testing array for gene loci associated with health risks, the chances are overwhelmingly that you will do nothing about the results. You could have saved your money and watched the last couple of minutes of Monty Python’s Meaning of Life, which tell you all you need to know about health behaviours.

Conquering coliforms
Another systematic review examines the global prevalence of antibiotic resistance in urinary tract infections caused by Escherichia coli in children. This confirms what we know from clinical experience: that the sensitivity of E coli to commonly used antibiotics changes in accordance with how commonly they are used. It’s a local game of cat and mouse. The mouse has the advantage of 3 billion years of experience at finding ways to resist antibiotics produced by other microbes, and the cat has the advantage of being able to switch antibiotics according to local patterns of resistance. During my working lifetime the only difference has been the appearance of fluoroquinolone antibiotics. Massively resistant forms of E coli are not about to take over the world. They will remain local and containable by very simple rules of antibiotic use.

Plant of the Week: Narcissus pseudonarcissus

Narcissus pseudonarcissus sounds like someone who appears narcissistic but is actually working for the common good. I could suggest a number of candidates from the world of medicine, but let’s concentrate tactfully on the wild daffodil, the true bearer of this name.

Being native to these isles, the daffodil knows how to cope with British weather. On mild days in January and early February, some daffodils came out in flower and have remained in flower ever since: their blooms seem amazingly weather-resistant. The remainder came into bud and have stayed that way for all the dull cold weeks which followed. We made our annual pilgrimage to Dymock to see the daffodil woods there last week. They were lovely, but many were still not in flower. I suspect they will be at their peak over Easter weekend, with the added bonus of wood anemones, of which we saw none.

I think local authorities should give away bags of wild daffodil bulbs for everyone to plant on road verges. These signals of spring banish the gloom of winter and must help to promote social harmony.