Richard Lehman’s journal review—8 May 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  3 May 2018

Triple inhaler for COPD

“Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate–vilanterol or umeclidinium–vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium–vilanterol. (Funded by GlaxoSmithKline).” says the abstract of this article.

But this message is accompanied by a cautionary commentary, co-authored by the editor of the NEJM, which saves me a lot of trouble by listing the defects of this trial:

“The results of the IMPACT trial are challenging to interpret because nearly 40% of the patients enrolled in the trial were receiving treatment with triple therapy, more than 70% were receiving an inhaled glucocorticoid, and patients with a history of asthma were included. Thus, for the patients assigned to the LAMA–LABA group, many of whom were actually stepping down in their treatment, inhaled glucocorticoids were abruptly withdrawn at the time of randomization; this could lead to COPD exacerbations. This design peculiarity, compounded by the probable inclusion of some patients who could have met a standard case definition of asthma, could explain the rapid surge in exacerbations observed in the first month after randomization in the LAMA–LABA group; during the subsequent 11 months of follow-up, the incidence of exacerbation with LAMA–LABA was practically identical to that with triple therapy.” The editors even go so far as to say that “Although single-inhaler triple therapy offers simplicity in treating COPD, any potential benefit could be lost and potential undue harm induced if triple therapy is expanded to patients with GOLD groups A, B, and C COPD.” Potential undue harm is a bit serious isn’t it? Shouldn’t editors bear this in mind before rather than at the same time as publishing an article? There are a lot of people with COPD.

Verubecestat fails to leave first base

Adverse events, including rash, falls, and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group.” Well, that doesn’t sound very nice. And just what might verubecestat be? It is an oral BACE-1 inhibitor that reduces the amyloid β level in the cerebrospinal fluid of patients with Alzheimer’s disease. “Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events. (Funded by Merck)” So just another failed Alzheimer’s drug, joining a hundred others in the would-be-blockbuster bin.


Reader, if like me you have spent a lifetime in medicine without ever having heard of calciphylaxis, here is your chance to find out about what you will probably never seeBut then if you look after people with advanced renal disease, you might: it is “a rare syndrome of calcification characterized by occlusion of microvessels in the subcutaneous adipose tissue and dermis that results in intensely painful, ischaemic skin lesions. Once calciphylaxis has been diagnosed, the prognosis is generally poor (survival, <1 year).”

JAMA 1 May 2018

Glibenclamide v insulin in gestational diabetes

Here in the UK we largely stopped using glibenclamide (called gliburide in the US) a couple of decades ago, thought the BNF still recommends it for lowering glucose if levels are high in the last two trimesters of pregnancy. The standard treatment for “gestational diabetes” is insulin, and this was the comparator in a French trial. Using a composite outcome measure including macrosomia, neonatal hypoglycemia, and hyperbilirubinaemia, they showed that there was no clinically significant difference between the twice daily oral glibenclamide and 4x daily insulin. However, they claim that insulin is superior, using the following statistical criteria: “The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, −∞ to 10.5%; P=.19).”

Five days of nitrofurantoin v fosfomycin in women’s UTI

Antibiotic “stewardship” means using antibiotics to best advantage, not spreading scare stories about universal resistance. One of the commonest reasons for antibiotic prescribing is to abort the painful and disruptive effects of bladder inflammation in women. Much of cystitis is caused by bacteria from the large bowel, which have been producing strains resistant to natural antibiotics for hundreds of millions of years. Nevertheless it is quite easy to kill them by switching around antibiotics in response to patterns of local resistance. Here’s a study from Switzerland, Poland, and Israel, which found that overall a five-day course of nitrofurantoin was more effective than a single dose of fosfomycin in those countries. Will this apply to the USA, where the article is published? For the UK, I much prefer a study which appeared a few months ago and shows a better grasp of context: “Results: Trimethoprim 200 mg twice daily (for 3 or 7 days) was estimated to be the most cost effective treatment (£70 per UTI resolved) when resistance was <30%. However, if resistance to trimethoprim was >30%, fosfomycin 3 g once became more cost-effective; at resistance levels of >35% for trimethoprim, both fosfomycin 3 g once and nitrofurantoin 100 mg twice daily for 7 days were shown to be more cost-effective.

Conclusion: Knowing local resistance levels is key to effective and cost-effective empirical prescribing. Recent estimates of trimethoprim resistance rates are close to 50%, in which case a single 3 g dose of fosfomycin is likely to be the most cost-effective treatment option.”

JAMA Intern Med May 2018

Becoming Kafka’s cockroach

Do get hold of this brilliant meditation on Kafka’s Metamorphosis, which shows how humanity can be taught through a story which is overtly unrelated to medicine. It will haunt your mind and expand its circumference, which is what great literature is meant to do. The article will take about ten minutes to read, and the Kafka about two hours. Some day you too may enter the closed side-room of the sick, and find yourself turned into something repulsive that people find hard to love and prefer to forget about. But while ever we can achieve it, the reverse metamorphosis is the important one.

“Each Man is in his Spectre’s power
Until the arrival of that hour,
When his Humanity awake..”

(hidden in an etching of Jerusalem by William Blake)

The Lancet 5 May 2018

Frailty, thy score is electronic

In the golden age of my memory, GPs would invite hospital consultants to visit patients in their homes. There was a certain etiquette: the GP would often drive the consultant to the patient and after introducing him/her, would allow the patient to lead, while bringing up the rear. The first important sign was that the patient couldn’t make it to the door. The next was that a cup of tea could not be offered. The next was that she couldn’t remember what pills she was taking, but they were in the kitchen, where a cupboard would spill a large collection onto the floor. The physical examination would consist largely of inviting the patient to walk across the room. “Frailty” and “multi-morbidity” never needed mentioning because doctors could still connect the two halves of their brains.

It’s different in hospitals. It seems you can derive a frailty score by simply looking at the electronic records. The authors of this study even imply that such a score derived from NHS hospital data is generalisable throughout the world. It can “identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful.”

More boring scoring

Healthy people need to be scored too, as we all know. Although a person’s cardiovascular risk score is just a very approximate pointer to what that individual may die from, based on population statistics, we’re constantly urged to refine these scores for discussion with individuals. I remember having this discussion briefly in the 1990s with Rod Jackson, when I was proposing that something or other might add value to a CV risk score. He persuaded me that this would have very little relevance to discussion with patients. But he doesn’t seem to have persuaded himself, and has studied to refine CV scores ever since. Here his team report on a prospective cohort study of 400,000 New Zealanders.

Cardiovascular disease is diminishing fast, and the old risk markers are becoming less important. Compared with most countries, the islands of New Zealand are heaven on earth, but social determinants still play a major role in CV risk there, and this score incorporates them. But how should we treat these determinants? I see that their PM is making a start, by promising a home for every homeless Kiwi throughout each winter.

Arrange to be born in Sweden

Unlike New Zealand, Sweden is not a place of balmy weather, abundant fruit, and general happiness. Yet its childhood mortality is one third that of Britain. The answer: less social inequality and deprivation, again. And again.

The BMJ 5 May 2018

Slippery baths for itchy kids

A tepid bath with blobs of emulsifying ointment floating in it. Then the ceremony of wrapping her legs in emollient bandages which she called “knee-cool”. Then more ointments before putting on her pyjamas, with sewn-on mittens to stop her scratching. Then the broken night, and in the morning the change of bedclothes streaked in blood. This is what looking after my daughter with eczema was like 35 years ago, and I don’t think it has changed much. Yet while there have been no major breakthroughs, there have been steady increments of knowledge, and here is one of them

Emollients are absolutely vital in treating childhood eczema, but if you are using them properly through the day, there is no added benefit in adding them to the bath. In particular, bath products which contain plant materials can actually worsen eczema.   

Figuring to improve colorectal cancer surgery

This study did not find evidence that the introduction of public reporting of surgeon specific 90 day postoperative mortality in elective colorectal cancer surgery has led to risk averse clinical practice behaviour or “gaming” of data. However, its introduction coincided with a significant reduction in 90 day mortality.” I admit to feeling uneasy when public reporting of individual outcomes was introduced, but I’m delighted that my fears were unfounded. Full marks to the colorectal surgeons, who have upped their game in response to openness.  

Plant of the Week: Acer pseudoplatanus“Prinz Handjery”

The plant we call the sycamore was introduced to Britain around 1500 and is now quite a tree-weed on these islands. I root out literally hundreds of seedlings each year in our small gardens. Patient nurserymen in the nineteenth century grew them on and propagated sycamores of every leaf-shade: those with purple leaves or white variegation are particularly fine. Others were valued for opening the season with striking pink-orange leaves, which look fabulous in the sunshine of early spring. I think ours is the greatest glory of our garden just now, and it has a lot of competition.

Nicholas Prinz Handjery (1836-1900) was a Prussian statesman of Russian birth who doesn’t seem to have done anything in particular to deserve his immortalisation in arboreal form. And I do think this tree will continue to be grown while ever there are gardens in the temperate world. It is out of fashion just now, like its close cousin “Brilliantissimum”. In the 1980s you would see these planted everywhere, like Robinia “Frisia”. Now they’ve grown too big for their suburban front gardens and been replaced, usually by infant magnolias. Gardening journalists have hastened their demise by describing them as two-week wonders that look wretched through the summer.

This is simply not true of Prinz Handjery. The glowing shrimp-coloured leaves continue to be produced sporadically through the season. In a week or two there will be lots of yellow flower-heads too. Admittedly the bulk of the green summer leaves with their purplish undersides can look rather gloomy, but they form a wonderful framework through which to grow viticella clematis varieties. In the autumn you get red sycamore wings. Come winter, you can try a bit of Prussian discipline on any excessive branches. As a result, ours stands stocky and neat through the bare months, only wanting a tight uniform and a silly helmet to look like the original Prinz Handjery himself.