Richard Lehman’s journal review—24 April 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  20 Apr 2017  Vol 376

Screening for retinopathy in type 1 diabetes

Lots of medical check-ups are timed to coincide with the earth’s orbit around the sun, and diabetic retinal checks are no exception. But how well does the periodicity of our planetary motion fit the need to look for neovascular changes and macular oedema in people with type 1 diabetes? Unsurprisingly, it bears no relation to it at all. Here’s a complex but highly practical modelling study based on two large cohort studies. During 30 years of the Diabetes Control and Complications Trial (DCCT) and its longitudinal follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, retinal photography was performed at intervals of 6 months to 4 years. From these databases, the investigators were able to calculate the rational interval for retinal examination at each stage of retinopathy. “Progression from states 1 or 2 to state 5 retinopathy was unlikely over a period of 4 or more years, but progression was highly likely over shorter periods in patients with moderate (state 3) or severe (state 4) nonproliferative diabetic retinopathy. Our data suggest that a practical, evidence-based schedule for time to the next examination would be 4 years, 3 years, 6 months, and 3 months for patients with states 1 through 4, respectively, for which the corresponding cumulative incidence of progression to state 5 retinopathy would be 2.9%, 3.7%, 6.6%, and 14.4%.” So it should soon be goodbye for annual eye checks in type 1 diabetes: how soon can someone do a similar exercise for type 2?

Eltrombopag! O put it in your doctor’s bag!

When eltrombopag first appeared as a synthetic thrombopoietin-receptor agonist, its name bound so tightly to my Edward Lear and Lewis Carroll receptors that an involuntary escape of nonsense verse occurred. There is danger that this new paper may induce another unfortunate emission.

Though inspiration starts to flag, for what could be unseemlier
Than jokes about eltrombopag and triflings with anaemia?
Eltrombopag, though only designed to stimulate the production of platelets, seems to have a wider effect on the bone marrow, which offers new hope to people with aplastic anaemia.
It’s serious news and cause to brag (most wondrous and fantastic)
That now we have eltrombopag for marrow-cells aplastic.

This article shows the results of eltrombopag given with immunosuppressive therapy to 92 consecutive patients with previously untreated severe aplastic anaemia. “At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted.” This is considerably better than previous results with immunosuppression alone, though it’s a pity the trial wasn’t a randomised comparison.

But when the blood counts zig and zag, in England or Bohemia,
Just get out your eltrombopag, and stop the dread anaemia.
Refrain: Eltrombopag! Eltrombopag! O keep it in your doctor’s bag!

Psoriasis: please don’t get mab with me

I’ve often called head-on trials between new agents in various diseases, and now I’ve got one. Please don’t get mab with me. Here’s one between two dose levels of ustekinumab and various doses of a new monoclonal antibody called risankizumab, in people with moderate-to-severe plaque psoriasis. Both inhibit interleukin-23 and the latter inhibits interleukin-12 as well. “The trial was funded by Boehringer Ingelheim and designed by the first author and the authors who are employees of Boehringer Ingelheim, as well as by other Boehringer Ingelheim personnel…The study-site investigators collected the data, and data analyses were conducted by Boehringer Ingelheim…Agreements between Boehringer Ingelheim and the authors included the confidentiality of the trial data. All the authors collaborated on writing the manuscript (with the assistance of a professional medical writer funded by Boehringer Ingelheim) and made the decision to submit the manuscript for publication.” Conclusion:”In this phase 2 trial, selective blockade of interleukin-23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety.” In case you were wondering, risankizumab is made by Boehringer Ingelheim.

Ularitide fails to turn the tide

Pity the failing heart. Above all, pity the person with a failing heart. From time to time, chronic heart failure will turn acute, causing pulmonary oedema and a sense of impending death from drowning. 2157 patients brought to hospital in this situation were randomized to receive either standard care or that plus an infusion of ularitide, which is a natriuretic peptide analogue. There was no difference in mortality or symptom control between groups. For those who follow such things, this paper brings a sense of dèja-vu: this was also true of nesiritide, a similar analogue, once it was properly trialled in 2011. As the editorial sagely remarks, “In reality, there should be no surprise here. Exacerbations of chronic disease reflect the chronic disease, not the hospitalizations used to manage those exacerbations.”

JAMA18 Apr 2017  Vol 317

Single-dose dexamethasone for sore throats

Here is a trial showing that a single 10mg dose of dexamethasone provides better symptom relief for sore throats than placebo. On the second day after administration. And by a very small margin. Nice though it is to see some Oxford colleagues published in JAMA, I’m not convinced that this should change clinical practice. It comes hard on the heels of last week’s BMJ paper showing an association between short-course steroids and a five-fold risk of sepsis. I imagine that the patients at highest risk of sepsis are those who are febrile when given steroids, though it would take a very large observational study to find out if this was true of people given dex for a sore throat. If you want another take on the pros and cons of this study, go to Ryan Radecki’s excellent blog.

Antidepressants in pregnancy and autism

Two large observational studies are discussed in an editorial with the title “Disentangling Maternal Depression and Antidepressant Use During Pregnancy as Risks for Autism in Children.”

Let this be a warning to you. Disentanglement of observational data is a dark art. To understand this stuff you need to be a Master of the Guild of the Holy Mystery of True and Unconfounded Interpretation of Observational Evidence, requiring a ten-year apprenticeship and the wearing of a special hat and socks. Is the diagnosis of autism in children associated with maternal use of serotonin reuptake inhibitors for depression during pregnancy? Yes, it is. Now, is this association caused by (a) depression in the mother, (b) the use of SSRI drugs, (c) genetics, (d) depressed mothers identifying their children as autistic, or (e) none of the above but some other confounding factor(s)? Not being initiated into the Holy Mystery, I really can’t tell you. You will have to read the Canadian study and the Swedish study and the editorial and then have a strong coffee and a long walk.

JAMA Internal Med  Apr 2017  Vol 177

Beta-blockers in pregnancy

So should we work from the assumption that to drug the mother is to poison the fetus? Perhaps that’s too drastic, but it always welcome to find evidence for the safety of drugs in pregnancy. Here’s a research letter about pregnant women who were taking β-adrenergic blocking drugs early in pregnancy. In unadjusted analyses, β-blocker use was associated with a higher rate of fetal cardiac anomalies. But when adjustment was carried out for maternal age, weight, and comorbidities, the association became non-significant.

Investigating microscopic haematuria

A cost-effectiveness study uses US data and costings to compare different diagnostic approaches to the investigation of asymptomatic people found to have 3 or more red cells in their urine. It is presented in such a way that I can make no sense of the figures, but you can have a go yourselves as the article is open access. The message is that CT scanning can safely be avoided and that the best tests are cystoscopy and ultrasound.

The Lancet  22 Apr 2017  Vol 389

Global Health: building a Heaven in Hell’s despair

It bothers me that I have nearly reached the end of my useful life without trying in any way to address the imbalance of medical care in the world. Not that it’s easy. There may be no political solution in sight. Here’s a Gates-funded survey of global health financing in 184 countries from 1995 to 2014, a time when the world has become immensely richer due to the runaway success of global capitalism. It has become immensely unfairer too. “Health spending remains disparate, with low-income and lower-middle-income countries increasing spending in absolute terms the least, and relying heavily on out-of-pocket spending and development assistance. Moreover, tremendous variation shows that neither time nor economic development guarantee adequate prepaid health resources, which are vital for the pursuit of universal health coverage.”

Nor is this likely to change in any consistent way, according to a forecasting paper repeating the message that economic growth alone may not solve the problem of inequity.

For every Bill Gates there seem to be fifty Donald Trumps. As Blake starkly described in “The Clod and the Pebble”, it is a question of whether the rich and powerful prefer to show true love or self love:

“Love seeketh not itself to please,
Nor for itself hath any care,
But for another gives its ease,
And builds a Heaven in Hell’s despair.”

So sung a little Clod of Clay
Trodden with the cattle’s feet,
But a Pebble of the brook
Warbled out these metres meet:

“Love seeketh only self to please,
To bind another to its delight,
Joys in another’s loss of ease,
And builds a Hell in Heaven’s despite.”

Songs of Innocence and of Experience Showing the Two Contrary States of the Human Soul (1794)

The BMJ 22 Apr 2017  Vol 357

Shared decision making and MAGIC

MAGIC in shared decision making comes in two completely separate forms. The MAGIC programme referred to here was the first one to arrive. The acronym stands for Making Good Decisions in Collaboration, and it was funded by the Health Foundation to design, test, and identify the best ways to embed shared decision making into routine primary and secondary care in the NHS, using quality improvement methods. This programme has now come to an end and this paper nicely summarizes its findings. The second MAGIC programme started with a group of evidence enthusiasts and stands for “Making GRADE the Irresistible Choice.” It is multinational and its funding model is quite different.  MAGIC.2 aims to provide tools through rapid evidence synthesis, and such decision sharing tools are badly needed. But as the original MAGICians point out, skills trump tools, and attitudes trump skills. What we are in for, over the coming decades, is a slow but profound shift of attitude: shared decision making will become part of every clinical encounter, and clinicians will be taught the skills to do it properly, from medical school and onwards throughout their lives. MAGIC.2 will provide some of the tools to make sure the information is sound and bang up to date. It will all be quite magical, darling.

Dexamethasone in your DREAMS

This seems to be the week for pushing dexamethasone. Let’s give 8mg intravenously to everyone undergoing bowel surgery. It makes them less likely to vomit afterwards, by a small degree (number needed to treat 5-22). Again, given the evidence that short-course steroids can promote sepsis, I’m a bit worried: bowel surgery followed by sepsis is not a pretty place, and we can’t judge safety from any but the biggest trials, or by observation when it is too late.

Healthy commuting

Sod Sitting, Start Walking says the title of Muir Gray’s latest book, written with Diana Moran. On my days at Cochrane UK, I am in constant danger from Muir walking or cycling or climbing the stairs with enviable vigour. I generally come by car. This is the trouble with living in the country, especially as I never learned to ride a bike. I can walk, and on a good day I can climb the stairs, but it is only when I stay in London that I get enough exercise. Commuting is good hard work. “Cycle commuting was associated with a lower risk of CVD, cancer, and all cause mortality. Walking commuting was associated with a lower risk of CVD independent of major measured confounding factors.” This comes from a prospective study of more than a quarter of a million people around the UK.

Plant of the Week: Clematis montana “rubens” 

Rubens is one of the earliest varieties of C montana to be grown in English gardens: the word derives from the Latin for pink, not from the painter of well-fleshed ladies. These May-flowering climbers decorate every Cotswold village, covering entire cottages and fully-grown trees. Approaching them on foot on a warm day, one is almost suffocated by waves of dusty vanilla scent. I have said all this before, but I will say it again. Provided it has scent, there is no such thing as a bad montana clematis.

Buy these plants now, so that you can smell them and check that you like their colour. I don’t mean just rubens, which is entirely dependable in these respects, but all the other varieties which have largely displaced the old trooper from garden centres. Some of them, like the double “Broughton Star”, verge on the sublime: others are a matter of individual taste. There is a tempting one called “Continuity,” which promises to flower right through the summer. Ours would, no doubt, but for the fact that it died shortly after being planted. By and large, montanas do not succumb to clematis wilt, but perhaps this one made an exception.

Montanas look beautiful covering anything, even a rusting tin-roofed shed. But you must try growing one over the large ceanothus called “Puget Blue.” Nothing can provide greater garden bliss in this season of promise and fulfilment.