Richard Lehman’s journal review—26 October 2015

richard_lehmanNEJM 22 October 2015 Vol 373
Neatest knee trial
1597 “Whatever next. A patient centred, surgical RCT on a common operation with a thoughtful, patient centred editorial in the NEJM,” wrote a friend on the day this paper appeared. Like minded messages and tweets poured in from both sides of the Atlantic. This randomised trial of total knee replacement is exactly the kind of trial that the US Patient Centered Outcomes Research Institute was set up to encourage. It’s exactly the sort of common and important question that the UK National Institute of Health Research tries to prioritise. But this trial was not funded by PCORI or NIHR. It was designed by orthopaedic surgeons in Aalborg University Hospital, Denmark, and it was funded by the Obel Family Foundation and a group of other public donors. One hundred patients were randomly assigned to undergo total knee replacement followed by 12 weeks of nonsurgical treatment, or to receive only the 12 weeks of nonsurgical treatment, which was delivered by physiotherapists and dieticians and consisted of exercise, education, dietary advice, use of insoles, and pain medication. A number of patient relevant outcomes were then measured over the next 12 months. Patients from the conservative treatment group could change to surgery within that time if they wished, but most of them did not. Nor was it a clear win for the group who were randomised to immediate surgery: their symptoms improved more, but they were at greater risk of serious adverse events, such as DVT and infection. So here we have a trial which, though small, is perfectly formed for shared decision making. This is an elective procedure that 670 000 Americans undergo each year. They are in a state of “dynamic equipoise” and what they need is objective information to help them decide when to have the operation. Here it is. I think each of the Aalborg orthopaedic surgeons who designed this trial should be given a new Porsche, to make up for the one they couldn’t afford because of a drop in their knee surgery income.

Kipling cancers and nicotinamide
1618 “Take up the White Man’s burden, Send forth the best ye breed,” wrote Rudyard Kipling in 1899, encouraging the US to do to the Philippine Islands as the British had done to the islands of Australia and New Zealand—occupy them at the expense of nearly extirpating their native inhabitants. Now the sun takes its revenge upon the peaceable descendants of those British white men, in the form of basal cell carcinomas and squamous cell carcinomas of the skin. When these occur in the former colonies, we could call them Kipling cancers. In fact, when I spent some months doing general practice in New Zealand, there was scarcely a person over 60 without one or two. “When we were kiddies we’d play in the sun all day, no hats or anything, and then I was cutting timber outside most of my life” was the typical story. Let them take nicotinamide, 500mg twice daily. Given to people in Sydney who had had at least two histologically confirmed non-melanoma skin cancers in the previous five years, this vitamin produced a reduction of 23% in the number of new non-melanoma skin cancers compared with a matched placebo group.

Eosinophilic neophytis
1640 Eosinophilic asthma, eosinophilic colitis, eosinophilic oesophagitis. These stain loving cells seem to be all the rage as a means of classifying hard to treat diseases. Eosinophilic oesophagitis, described in this review, is the kind that usually doesn’t get better with proton pump inhibitors. “It has been described in all age groups, but it predominantly affects white men, with an onset from school age to midlife.” Kipling oesophagitis, then. It is defined by its histology, though with slightly imperfect precision: “A cutoff value of at least 15 eosinophils per high power field is thought to approach a sensitivity of 100% and specificity of 96% for establishing the histologic diagnosis of eosinophilic esophagitis.” I like the “thought to”—it would be nice to know how stable and reproducible these biopsy findings are. It is certainly hard to beat a clear path through this review, and the only treatment option seems to be budesonide, given in a form designed to maximise local contact with the oesophagus.

JAMA 20 October 2015 Vol 314
Pointless pills for backache
1572 Last week it was physiotherapy for acute low back pain: this week it’s additional analgesia. It’s the same story: a randomised trial confirms the uselessness of something that we knew was probably useless. It measured functional outcomes and pain at one week and three months after an emergency department visit for acute low back pain among 323 patients randomised to a 10 day course of (1) naproxen + placebo; (2) naproxen + cyclobenzaprine; or (3) naproxen + oxycodone/paracetamol. The additional analgesics made no difference compared with naproxen alone. Back pain can be truly horrible, so it would be good to hear a more positive message. But treatment can only advance as we undeceive ourselves about the drugs we often prescribe “just in case they might help.” In the case of oxycodone and other opioids, they are far more likely to harm.

Pre-eclampsia and heart defects
1588 Medicine will never be a perfect science, but at least it is a cumulative one. If there was a strong association between pre-eclampsia in the mother and congenital heart problems in the baby, we would have known about it by now. By looking at the entire population of Quebec, i.e. a quarter of the population of Canada, investigators were able to discover weaker associations. The absolute prevalence of congenital heart defects was higher for infants of women with pre-eclampsia (16.7 per 1000) than infants of women without it (8.6 per 1000). Among specific defects, prevalence was greatest for septal defects. How you subclassify these results depends on your statistical belief system. For readers with nothing better to do on a dull afternoon, here is a statement to argue about: “Infants of pre-eclamptic women had no increased prevalence of critical heart defects (123.7 vs 75.6 per 100 000 [90/72 782 vs 1414/1 869 290]; PR, 1.25; 95% CI, 1.00 to 1.57; prevalence difference [PD], 23.6 per 100 000; 95% CI, −1.0 to 48.2) but did have an increased prevalence of noncritical heart defects (1538.8 vs 789.2 per 100 000 [1120/72 782 vs 14 752/1 869 290]; PR, 1.56; 95% CI, 1.47 to 1.67; PD, 521.1 per 100 000; 95% CI, 431.1 to 611.0) compared with infants of non pre-eclamptic women.” Question: how many defects would have to be reclassified as “critical” to knock out the “no” before “increased prevalence” in this sentence?

Lancet 24 October 2015 Vol 386
Now please wash your hands
1631 A moderately intensive, web based intervention to encourage hand washing over a four month period reduced the reported incidence of upper respiratory infections within households by 8% in the course of a research study based in UK general practice. Both the paper itself and the related editorial speculate on how this might be translated into a population strategy. The study authors mention possible usefulness in an influenza pandemic. The editorialist suggests that a different, community based programme might be more effective. None of these questions can be addressed by the trial as conducted, though it gives us some evidence that hand transmission plays a part in spreading respiratory viruses within the home during non-pandemic years.

Shin nerves and rear end problems
1640 Why should stimulating the tibial nerve help people with faecal incontinence? Well, the argument runs that we know that sacral nerve stimulation does work, and “percutaneous stimulation of the tibial nerve (PTNS) is thought to lead to similar changes in anorectal neuromuscular function as with sacral nerve stimulation because of shared sacral segmental innervation.” But doesn’t that logic run in the wrong direction? Anyway, the investigators started as all researchers should, and did a systematic review of previous studies. Existing trials showed that the success rate of PTNS in the treatment of faecal incontinence ranged from 52 to 82%. So they went on and designed a good sham controlled study, which they managed to give the acronym CONFIDeNT by torturing the constituent words until they confessed. Result: “PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence.” I actually feel quite relieved: I like to think I can tell my anal sphincter from my shinbone, if I may say so.

Eltrombopag! Eltrombopag! O keep it in your doctor’s bag!
1649 I love nonsense words, and gabble them away to myself in a most embarrassing way, but I must hand the palm to whoever invented the word “eltrombopag.” It is better than anything I have ever come up with, even in the bath. When it first appeared in 2007, I wrote a little song about it with the refrain “Eltrombopag! Eltrombopag! O put it in your doctor’s bag!”, and when it reappeared in 2011, I wrote another one. But it would be too much trouble to look them up now. So what is eltrombopag, I hear you ask. It is a thrombopoietin receptor agonist and here is a trial in children with chronic immune thrombocytopenia. To enrol 92 children for a 13 week trial, GlaxoSmithKline used 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and the US). “Authors employed by the funder of the study contributed to the study concept and design, data interpretation and analysis, and final approval to submit for publication. The study funder provided funding for editorial assistance for manuscript preparation.” Just in case you thought such practices were a thing of the past in these enlightened times. The drug was a success for 40% of the children and it was continued for another 24 weeks for safety monitoring. Eltrombopag is available in 28 tablet packs containing 25 mg tablets (£770) or 50 mg tablets (£1540). Actually, I wouldn’t keep it in your doctor’s bag—better to deliver it in an armoured vehicle.

Ode to Music
1659 “What Passion cannot MUSICK raise and quell?” asked Dryden in A Song for St Cecilia’s Day, 1697. The authors of this systematic review came at it a little differently: “Music is a non-invasive, safe, and inexpensive intervention that can be delivered easily and successfully. We did a systematic review and meta-analysis to assess whether music improves recovery after surgical procedures.” They included 73 RCTs in the systematic review, with size varying between 20 and 458 participants. Choice of music, timing, and duration varied. Comparators included routine care, headphones with no music, white noise, and undisturbed bed rest. Music reduced postoperative pain (standard mean difference −0.77) anxiety (−0.68 ), and analgesia use (−0.37 ), and increased patient satisfaction (1.09), but length of stay did not differ (SMD −0.11). This gives Paul Glasziou the opportunity for a delightful editorial about the therapeutic power of music. Choice does matter, however. At the end of Dryden’s Ode, a trumpet sounds and “The dead shall live, the living die, And MUSICK shall untune the Sky,” which might prove inconvenient on the postoperative ward.

The BMJ 24 October 2015 Vol 351
Not like a stoma catalogue
Over a decade ago, Richard Smith famously said that he wanted The BMJ to become less like Brain and more like Cosmopolitan. For the British doctors who get it through the post each week as part of their BMA subscription, this has now come true. It’s bright, zappy, abundantly illustrated, and full of short and interesting items. The downside is that the advertisements and the text are now almost indistinguishable, but aesthetically it is nothing like the futuristic issue that Smith brought out to shock people in the early 2000s. I described it at the time as looking “like a stoma catalogue that someone has been sick over.” The new BMJ—more correctly thebmj—is nice to handle and read, if just a bit too busy. Academics who ask how it can at the same time aspire to be a world class research journal have a point, but that won’t depend on any print format but on the choice of research papers. For example, it could be the world’s leading publisher of high class qualitative research if it would show as much imagination in its selection criteria as in its paper dress.

Radiation over time
Here’s a study timed to coincide with the UK government’s decision to go ahead with two new nuclear power stations, under Chinese/French government auspices. At the same time the UK wants to keep its nuclear weapons programme, just in case some government such as China or France cuts up rough. All these facilities will expose workers to low dose ionizing radiation over many years. In this cohort study, 308 297 workers in the nuclear industry from France, the United Kingdom, and the United States with detailed monitoring data for external exposure to ionising radiation were linked to death registries. Excess relative rate per Gy of radiation dose for mortality from cancer was estimated. Rather to my surprise, this confirms the traditional assumption that the risk per unit of radiation dose for cancer among radiation workers is similar to estimates derived from studies of Japanese atomic bomb survivors.

Helpful observations
When you’ve had your heart attack, you go home with a little bag of medications. These will doubtless include aspirin and, if you have had a drug eluting stent, clopidogrel as well. I’d call these antiplatelet agents but this Danish study calls them antithrombotics. Now we know that if you add a non-steroidal anti-inflammatory drug (NSAID) to one or both of these, the risk of a gastrointestinal bleed is quite considerable. So when it seems necessary to prescribe a NSAID, GPs in Denmark (as in England) often add a proton pump inhibitor. This population registry study seeks to discover if this actually reduces the risk of bleeding. And yes, it does. Information like this is very useful in situations where it would be very difficult to do a randomised trial.

Music of the Week: Handel’s Ode for St Cecilia’s Day

Since I strayed into quoting from Dryden’s Ode celebrating the power of music, I’ll just say that there are several recorded “modern” versions of Handel’s marvellous setting, but for a thrilling example of an older performing style, try the live recording Benjamin Britten made in 1967. I think you can find it on a single CD costing about £14, but while you’re about it, why not go for the 27 CD Decca set called “Britten the Performer.” It’s full of wonderful things at less than £2 a disc. As Stravinsky famously remarked when asked what he thought of Britten, “he’s such a marvellous accompanist.”