Richard Lehman’s journal review—7 March 2016

richard_lehmanNEJM  3 Mar 2016  Vol 374

Inducing for better outcomes?
813 This useful British trial was done with the ultimate aim of reducing stillbirth, which tends to happen more in women who give birth for the first time at the age of 35 or older. The presumption is that induction at term will reduce the stillbirth rate, but critics have said it would increase the rate of caesarean delivery. This trial did not use stillbirth as an end-point: there are 3,600 stillbirths per year in the UK, which is a lot, but still means that you would have to randomise half the country to get a definitive result. So 619 nulliparous women aged 35 and over were randomly assigned to labour induction in the last week of gestation, or to expectant management, and the primary outcome was caesarean section. In fact there was no difference in the CS rate between the groups, so in theory a very large trial of induction to prevent stillbirth could go ahead.

Cotrimoxazole after abscess drainage
823   Ancient GPs will remember the good old days of Septrin and Bactrim. These whopping trimethoprim-sulfamethoxazole pills would deal with most things provided patients could swallow them. But because the sulfa component caused frequent allergic reactions, they fell out of favour except for preventing pneumocystis pneumonia in HIV infected people. Cotrimoxazole is now staging a come-back because it is unexpectedly good at dealing with meticillin-resistant Staphylococcus aureus. MRSA is more of a problem in the USA than in the UK, and besides that nobody really knows if giving antibiotics is beneficial after you have drained a skin abscess. So a randomised trial of cotrimoxazole following drainage of skin abscesses in areas of high MRSA prevalence was done in US emergency departments. And it did indeed result in a slightly better healing rate and a usefully lower rate of recurrences.

Kids who survive cancer
833   It’s a let’s-not-go-there place: a kid survives cancer, only to die in the prime of life from a second cancer or late heart failure induced by the treatment that cured the first. The bad news is that 6% of people who were cured of cancer before the age of 21 in the USA still die in the next 15 years; the good news is that this is half of what it was for youngsters treated in the 1970s. These figures come from the 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer. Nearly half the deaths are from subsequent neoplasms.

Zika & pregnancy: as we feared
OL   Here’s a prospective study of Zika virus infection in pregnant women which reports results up to and including February 2016. It rode on the back of an existing febrile disease surveillance project run by the Oswaldo Cruz Foundation and the University of California, Los Angeles. Reports came in during 2015 of a dengue-like illness that was characterized by rash, fever, myalgias, arthralgias, and conjunctivitis. As we know, it coincided with a wave of microcephalic births and was discovered to be due to an obscure African arbovirus discovered long ago in a forest called Zika. Here they were able to enrol 88 pregnant women and use a reasonably specific PCR test for ZIKV on blood and urine samples. “Our findings are worrisome because 29% of ultrasonograms showed abnormalities, including intrauterine growth restriction, CNS findings, and fetal death, in fetuses of women with PCR-positive ZIKV infection.” So Zika is indeed powerfully harmful to the fetus. Also bear in mind that these abnormalities are just the ones gross enough to show up on ultrasound, and brace yourselves for the possibility of worse news when long-term neurodevelopmental data trickle in over coming years.

JAMA  1 Mar 2016  Vol 315

NovoNordisk modesty
898 “Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes.” My countenance darkened when I saw this title, and went a shade blacker when I looked at the place where JAMA buries the sponsorship details: “Novo Nordisk was involved in the study design and protocol development, provided logistical support, and obtained the data, which were evaluated jointly by the authors and the sponsor.” To collect just 557 patients, the company used 78 centres in 10 countries: about 7 participants per centre. “Uncontrolled” T2DM meant having a HbA1c of 8-8.5 %, which does seem a reasonable point to consider intensifying treatment in these fairly young (mean age 58.8) patients. And the NovoNordisk combination product of once-daily degludec insulin plus liraglutide showed three advantages over increased doses of glargine insulin: less nocturnal hypoglycaemia, no weight gain, and a lower final HbA1c. It’s interesting that NovoNordisk don’t flag up these advantages much in the abstract or the conclusions. Maybe we are at the stage of “reverse marketing”: soft-pedalling on the hype and using the graphics in the paper to persuade clinicians. All in all, this trial was not as bad as I had expected: my countenance brightened a little as I went through it, though of course we still don’t have a clue about what this new combination drug does for the long-term outcomes that matter.

JAMA Intern Med  Mar 2016

Crashing out in Denmark
OL   All six million or so citizens of the kingdom of Denmark are tracked from birth to death. Don’t think you can faint and be taken to hospital there without it being noted by an epidemiologist and linked with subsequent motor vehicle crashes. This paper shows that Danes who have had syncope are almost twice as prone to crash their cars subsequently.

Flibbing waste of time & money
OL   Hypoactive Sexual Desire Disorder in Women is rife among the American female population. The situation may have improved over recent days, owing to Donald Trump’s mention of his membrum virilis, but we cannot expect the effect to last. In the view of Sprout Pharmaceuticals, a better answer is flibanserin. Undeterred by two rejections from the US Food & Drug Administration, they formed a lobbying group and succeeded in getting the drug approved for this indication at the third attempt and against the advice of the FDA’s own clinical review teams. Two days later they sold the drug to Valeant Pharmaceuticals for about $1 billion. The tale is superbly told by Steven Woloshin and Lisa Schwartz.

In this systematic review, the true effects of flibanserin are all too clear. For the chance of one extra satisfactory sexual experience every two months, you have to avoid alcohol altogether and run a high risk of dizziness, somnolence, and nausea. Interactions with common drugs like fluconazole can cause profound hypotension and loss of consciousness. At least if the earth has not moved for you, you will have moved towards the earth.

Lancet  5 Mar 2016  Vol 387

Carotid choices according to age
OL   Papers continue to pile up on The Lancet website, and although I’m only three weeks in arrears, I risk bringing you old news. Last week I gave you the long-term results of the Carotid Revascularization Endarterectomy versus Stenting Trial from the NEJM, and said that outcomes were so similar that it was almost impossible to make a choice. Here’s an individual participant data meta-analysis (hurrah!) from four such trials. And this time there is a clear message for those over 70: go for endarterectomy and not for stenting, because the latter doubles your risk of a periprocedural stroke. This is a beautiful example of how good shared decision making depends on well-synthesised and well-analysed evidence.

Can’t do right for doing wrong
OL   Gastric diversion surgery is extending the lives of hundreds of thousands of people and is bound to remain popular until we come up with something better. But it definitely ain’t natural. If you perform it through a laparoscope you are bound to leave a hole in the mesentery, through which the small intestine may then herniate and obstruct itself at any time in the future. Would it be better if surgeons were to close the mesenteric defect as a routine part of laparoscopic gastric bypass surgery? The conclusion of this big Swedish trial is that they should. Defect closure increases the length of the operation by about 13 minutes and the rate of post-operative complications from 7% to 8%, often due to early small bowel obstruction caused by kinking of the jejunojejunostomy. But over the following three years, more than three times as many patients needed operative treatment for small bowel obstruction if they had not had the mesentery closed.

Striking stroke advance
OL   Last year, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. Now this is big. And already the HERMES collaboration has done a meta-analysis of individual patient data from five randomised trials. Kudos to the mighty elves of Hermes! Just in case you imagine that there are grown-ups in charge of trial acronyms, these five are called MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA. So sweet. Now off you go, it’s past your bedtime. The conclusion of the meta-analysis is:

“Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion.” The first sentence would only be strictly true if the effect of thrombectomy was evenly distributed, which it isn’t, but it is still very impressive: “The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on the modified Rankin score for one patient was 2·6.” As for the effect of this evidence on service provision, that’s a worthy prospective mapping exercise for a whole bunch of other mighty elves.

Antibiotics & the Mencken Effect
OL   “Conscience is the inner voice that warns us somebody may be looking,” said HL Mencken. There was a nice illustration of the Mencken effect on antibiotic prescribing in US primary care in JAMA three weeks ago and here comes one from UK primary care, under the aegis of Sally Davies, Chief Medical Officer for England. GPs who were in the top quintile of antibiotic prescribing were sent messages to tell them that somebody was looking, and their conscience did the rest. “Inappropriate” antibiotic prescribing for respiratory infections fell, from 24.1% at baseline to 13.1% eighteen months later. In fact this kind of prompting about antibiotics has gone on in Oxfordshire since about 2008. And as a paper on the website of Thorax points out, “Hospitalisations for community acquired pneumonia have been increasing rapidly in Oxfordshire, particularly since 2008. There is little evidence that this is due only to changes in pneumonia coding, an ageing population or patients with substantially less severe disease being admitted more frequently.” Most of these infections are caused by bacteria susceptible to common antibiotics. I am not drawing any inferences, just pointing out that if I were the CMO, this is something I would like to look into.

BMJ  5 Mar 2016  Vol 352

Finnishing with coronary heart disease
It is the most remarkable case of dogs not barking. Wonderful things are happening in cardiac epidemiology, but where are the wuffs of delight? Here are the stats from Finland: “During the 40 year study period, levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969-1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100 000 people) and 84% (114 to 17) among men and women aged 35-64 years, respectively.” There’s a lot of analysis using known correlation sizes in relation to serum cholesterol, smoking and blood pressure, but that still doesn’t explain a third of this staggering reduction. People have grown fatter, and alcohol consumption in Finland has doubled in that period. I’m only saying…

Cancers due to prostate radiation
OL Here’s a useful review of the literature estimating the risk of getting a second malignancy after radiotherapy for prostate cancer. For brachytherapy it is low—sometimes, strangely, less than in the control group. For external beam radiotherapy, estimates of absolute risk increases vary widely. For bladder cancers, between 0.1 and 3.8%. For colorectal cancer, between 0.3 and 4.2%.

Plant of the Week: Cornus mas “Variegata”

 There are at least three variegated dogwoods which every garden should have. The most striking in leaf are the fabulous C alternifolia with tiers of branches, and its larger cousin C controversa. But for longer season interest, and edible fruit, you also need the variegated form of the cherry cornel, which the Roman legions brought to these islands two thousand years ago.

C mas is an untidy small tree which produces abundant small tart cherry-like fruits in October. Its variegated form is too small to be called a tree at all, but it produces the same fruit, and I suppose if you went into the posh dining trade you could grow groves of them to make unusual pastes and preserves for Michelin-starred restaurants. The “cherries” are very easily picked or shaken from the tree when ripe.

The reason I’m telling you about this plant in March is that it’s currently covered in little tufts of yellow flower which make it look quite pretty, long before the white-edged leaves appear. The smell of these has a bite about it, and we’ve come to associate it with the sharp winds of March. A bit of edge, but a lot of promise.