Richard Lehman’s journal review—11 June 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  7 June 2018

Missed miscarriage: two drugs better than one

Unsuccessful pregnancy is a difficult thing to talk about. That’s reflected in the rather awkward language of this paper and my subheading. I remember the days when the approved technical terms included “blighted ovum” and “incomplete abortion”, horrific words to be overheard by mothers undergoing the mental trauma of knowing their pregnancy was at an end. Even today the title of this article in the New England Journal refers to “early pregnancy loss” when it really means pregnancies which are non-viable, but not yet lost. In this situation of early fetal death or an anembryonic pregnancy detected on ultrasound, intravaginal misoprostol is the standard management, but when used alone it fails in about a third of cases. This randomised controlled trial shows that if 200mg of mifepristone is given by mouth the day before, the success rate of misoprostol treatment goes up from 67% to 84%. The treatment of “missed miscarriage” has become more effective thanks to a simple publicly funded trial using cheap drugs.  

A use for bezafibrate

When bezafibrate was used to lower lipids by lipidologists, my chief role used to be to see the patients afterwards when they complained of muscle aches, abdominal pain, and bloating and tell them that it didn’t matter if they stopped it. Now it emerges that the only patients who really should take bezafibrate are those with primary biliary cholangitis. A French trial in 100 patients shows that patients whose liver enzymes fail to normalise with ursodeoxycholic acid have a very high rate of biochemical remission when given added bezafibrate compared with those given placebo (both groups continuing ursodeoxycholic acid). This is a surrogate, of course, but a very promising finding. And in this study the only major adverse effect was muscle pain—10% in the placebo group and 20% in those taking bezafibrate.

Please share my data

In only six years, we’ve won the battle for the principle of full sharing of datasets from clinical trials. Some of the counterarguments have died away—e.g. that the triallists have a moral right to the data they collected, that only they can interpret it, or that it will be misused for frivolous or litigious purposes. But among the more serious objections is the idea that some trial participants do not wish for their data to be more widely used, even when anonymised. In the past, consent was not obtained for such use. An interesting survey of 771 current and recent participants from a diverse sample of clinical trials at three academic medical centres in the United States. 93% of respondents were happy for their data to be shared. The respondents’ greatest concerns were that data sharing might make others less willing to enrol in clinical trials (37% very or somewhat concerned), that data would be used for marketing purposes (34%), or that data could be stolen (30%). Less concern was expressed about discrimination (22%) and exploitation of data for profit (20%).  

JAMA 5 June 2018

How much oxygen for very premature babies?

The last time I was in a special care baby unit was in 1978, when I worked a 1 in 2 paediatric rota. All night long we stabbed these poor tiny infants to get blood gas measurements. The burning question then was how much oxygen to give them to maintain good saturations and avoid necrotizing enterocolitis while avoiding retinal damage from too much. Now, forty years later, we have another study of this very question, which is still partially unresolved. It takes the form of a prospectively planned meta-analysis of individual participant data from extremely preterm infants. There was no significant difference between a lower SpO2 target range compared with a higher SpO2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower SpO2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.   

Mandatory shared decision making

For certain irrevocable medical and surgical decisions, informed consent has long been a mandatory ethical standard. Even in the Nazi era, a Jewish prisoner successfully used it to resist her forcible sterilisation in a concentration camp, and a huge literature on the subject followed the Nuremberg Medical Trials in 1946, summarised in the various versions of the Helsinki Declaration since. Here’s a discussion piece triggered by the increasing trend for the US Centers for Medicare & Medicaid Services (CMS) to make shared decision making a condition of coverage. This extends to some forms of diagnostic procedures and screening as well as surgical procedures and some medicines. Examples include lung cancer screening with low-dose computed tomography and left atrial appendage closure for stroke prophylaxis in atrial fibrillation but may shortly extend much more widely. Passionate though I am about better-informed conversations between health professionals and autonomous individuals, I am not sure widespread compulsion is a good thing. Expect more on this subject once I have “retired” from writing these reviews and get seriously boring.

JAMA Intern Med June 2018

Metformin and lactic acidosis

It’s a pleasure to see good observational methods brought to bear on a question that has bugged clinicians for the whole of my working lifetime. At what point does it become hazardous to use metformin in people with renal disease? Here’s that answer: “In two real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30mL/min/1.73m2.Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30.”

As someone who’s been trying to preach the idea of involving people with so-called type 2 diabetes in decisions about their treatment, I’m delighted to see that the linked editorial concludes:

“We believe that when presented with a balanced risk benefit discussion of all 3 agents, many if not most patients will choose metformin as the first-line drug in the setting of CKD. The challenge is for clinicians to present clear information to guide patient decisions, based on each patient’s clinical circumstances and preferences.”

Ann Intern Med 5 June 2018

Shock horror: CV risk scores change over time

Rates of coronary heart disease in developed countries are tumbling down and any cardiovascular risk score is obsolescent within a few years. Not that doctors in the UK take much notice of them anyway. But they probably should, especially before prescribing statins. So should US doctors, bearing in mind this latest study:

“The 2013 pooled cohort equations overestimated 10-year risk for atherosclerotic CVD by an average of 20% across risk groups. Misestimation of risk was particularly prominent among black adults, of whom 3.9 million (33% of eligible black persons) had extreme risk estimates (<70% or >250% those of white adults with otherwise-identical risk factor values). Updating these equations improved accuracy among all race and sex subgroups. Approximately 11.8 million U.S. adults previously labeled high-risk (10-year risk ≥7.5%) by the 2013 PCEs would be relabeled lower-risk by the updated equations.”

The Lancet 9 June 2018

Dabigatran for MINS

Another week, another acronym. MINS stands for myocardial injury after non-cardiac surgery. And here was me thinking it stood for minimally invasive nit-slaying. If troponin levels go up after non-cardiac surgery, so does the risk of future major vascular events. The makers of dabigatran randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877), and (bearing in mind a permanent discontinuation in 46% of 877 patients allocated to dabigatran and 43% of 877 patients allocated to placebo) there was a 4% absolute reduction in the composite primary outcome over 2+ years. The conclusion reads: “Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 100 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication.” With The Lancet letting through a sentence like that, who needs a marketing department? It’s not as if there was even a comparator like, say, aspirin.

The BMJ 9 June 2018

Swotty and bespectacled

My myopia was detected by screening at the age of six, so it can’t be put down to my inordinately lengthy process of education, which continues even now, albeit with ever-diminishing success. All my life I have been swotty and bespectacled, but it still took me till 67 to become a professor. Here’s a Mendelian randomisation study which suggests a unidirectional association between years in education and short-sightedness; though clearly this doesn’t apply to me, since I hadn’t read a book by the age of 6. By that age, John Milton had probably read all of Homer and Virgil in the original, by candle-light. His spiteful contemporaries were quick to see his blindness as a punishment. For that and regicide.

Plant of the Week: Robinia hispida

The commoner kinds of flowering tree have gone to seed now, but the robinias are in full flower in England, and I can’t remember a better year for them. Some are almost entirely white with blossom. A fully grown robinia can be about 20 m high and trees of this size are quite spectacular at present. Look up: there may be one near you. Their racemes of hanging blooms look and smell very similar to those of white wisteria. O to be a bird sitting high in a robinia on a sunny afternoon. The fragrance from ten thousand flowers might make me swoon and fall off my perch. But I would soon recover, and fly back to my high and perfumed bower.

The seed-pods which follow the flowers are a reminder that both these mighty classes of plants—robinias and wisterias—belong to the pea family. These twisty fruits give the tree its English common name, the false locust.

In France, robinias line every street. They bear a few mean flowers and insist on being municipal. They are stunted from receiving too little water and too many cigarette butts. Their furrowed bark is full of dusty ennui.

There are many varieties and species of robinia, the most popular of which was a yellow-leaved clone called “Frisia”. Unfortunately it rarely bears a single flower, and people who planted it in the 1980s have since grown bored with it and use the space for something else. There are pink varieties of robinia which look lovely in pictures and flower most attractively at an early age. But they never grow old because their boughs are insanely brittle and shear off at the first serious puff of wind.

The moral of this is that unless you own a large tract of parkland, don’t plant your own robinia. Enjoy other people’s from a safe distance.

Could you write a weekly journal review?

Richard Lehman will be retiring from writing his weekly reviews in the Summer 2018. We are looking for someone to replace Richard and write a weekly journal review. We are interested in candidates with excellent knowledge of research and critical appraisal, and an understanding of how research impacts on clinical practice.

We are particularly interested in candidates who have clinical experience and an excellent standard of English. You must be motivated, creative, and able to write the weekly reviews to a tight deadline every week.

This freelance position offers a salary per column.

Please apply with a CV and covering letter and an example of how you would write a research review.

Please send applications to: Juliet Dobson, Digital content editor, The