Richard Lehman’s journal review—13 February 2017

richard_lehmanNEJM  9 Feb 2017  Vol 376
Middle East Respiratory Syndrome
Remember MERS? It was the talk of the town five years ago when it was first identified in Saudi Arabia. There were a number of deaths and some evidence of human to human spread, causing widespread concern. But although it can be a nasty and fatal infection, it is no killer plague. Cases have been reported in 23 countries, but so far there have been fewer than 700 attested deaths, 80% of them in Saudi Arabia. Because it remains relatively rare and sporadic, nobody is in a great hurry to market a vaccine against the coronavirus MERS-CoV. Prevention consists of avoiding dromedary camels, especially if they look a bit peaky. If you need to know more, this excellent review will help you to mount your desert steed and survey the full landscape.

JAMA  7 Feb 2017  Vol 317
Sickle cell trait protects against pre-diabetes
Sickle cell trait has long been known to protect against malaria, which plausibly explains its prevalence in Africa. But in the 21st century it has an additional protective effect against the epidemic of diabetic labelling. Investigators looked at two cohorts of African Americans who had concurrent measurements of blood glucose, sickle cell haemoglobin variants, and glycated haemoglobin (HbA1c). Comparing measurements of fasting glucose or glucose tolerance with levels of HbA1c, it turned out that people with sickle cell trait produced systematically lower readings than people without. So people with this trait are at reduced risk of being labelled as having “pre-diabetes” or “type 2 diabetes” on the basis of having some borderline level of HbA1c.

JAMA Intern Med  Feb 2017
Metronidazole v vancomycin for C diff
Metronidazole achieves the same reduction in recurrence of Clostridium difficile as oral vancomycin but is more than 10 times cheaper. So why not use metronidazole as firstline treatment for everyone?  Because, according to this retrospective, propensity-matched study of patients in the US Veterans’ system with confirmed C diff, more of the sickest patients will die. The full article seems to be open access and also provides a useful overview of primary oral antibiotic treatment for this infection, which has changed little over the years. The message of all the trials and systematic reviews is that if your patient with C diff looks sick, go for vancomycin.

Ann Intern Med  7 Feb 2017  Vol 166
Carcinogen reduction in e-smokers
We have plenty of long term data about smoking tobacco, but we don’t have long term data about e-cigarettes. We know that for many they are a useful aid in overcoming nicotine addiction, but since nicotine is one of the most addictive substances known, some e-cigarette users are likely to carry on using them for decades. Until decades have elapsed, we’ll have to extrapolate from what we know about the carcinogens in tobacco smoke as compared to e-cigarette vapour. Here’s a study funded by Cancer Research UK, which tried to measure these toxins. The results confirm common sense: people who continue smoking show much higher levels of known toxins and carcinogens in their saliva and urine than people who use nicotine replacement therapy, either as e-cigarettes or other products. And, overall, they get roughly the same amount of nicotine.

Metformin the good
For decades, nobody had a bad word to say about metformin, except some patients who couldn’t stand the bloating and diarrhoea. Recently, there have been various murmurings against its alleged superiority to other glucose lowering agents, but the latest evidence review points to a mortality benefit—especially in the very people who were traditionally warned against taking it. The reviewers looked specifically at people with type 2 diabetes who also had moderate to severe kidney disease, liver disease, or chronic heart failure. The observational studies show a reduction in mortality and readmission with heart failure. But beware: there is so much room here for confounding by indication, and the reviewers rate the strength of evidence as low, with missing outcome data and variable duration of follow-up.

Lancet  11 Feb 2017  Vol 389
IA steroid only for oligoarticular juvenile arthritis
Oligoarticular juvenile idiopathic arthritis? Like when a kid gets a swollen inflamed joint (or two) and nobody can work out why but jumbles together some Latin and Greek to hide their ignorance? Most GPs will have seen a case or two, and in Italy they collected 207 children with this diathesis (another good word to use if you’re stuck), and randomised them to receive either just intra-articular corticosteroid injections or IA steroid plus oral methotrexate. Their primary outcome was the proportion of patients in the intention to treat population who had remission of arthritis in all injected joints at 12 months, and it did not differ between groups. It’s a pity that there wasn’t a third group in which the long acting steroid injections were given in random locations: I suspect the results would have been the same.

Schizophrenia trials
I have yet to read an article about drugs for schizophrenia that hasn’t filled me with dismay. I hear voices saying, “what a load of crap”—sorry for the language, but these voices can be very blunt. I become delusional, thinking that when I am God there will be proper trials with clear recruitment criteria, patient important endpoints, and good levels of follow-up. I become paranoid, looking over my shoulder to see if there is a pharma agent who wants to kill me for suggesting that trials are designed to market new drugs rather than help psychotic people. Finally, I become apathetic. At this point, I am randomised to receive either cariprazine or risperidone for my “predominant negative symptoms of schizophrenia.” At the end of the trial I don’t feel any different, but I am comforted to learn that “Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (−8·90 points for cariprazine vs −7·44 points for risperidone; least squares mean difference −1·46, 95% CI −2·39 to −0·53; p=0·0022; effect size 0·31).” That is a difference of 1.46 on a scale of 49. “Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia,” say the authors from this industry funded trial. Yes, slightly, and not in comparison with the cheaper alternative drug.

Polypill for high blood pressure
There is hardly any primary research to report from the main journals this week, but scouring the Lancet website, I find a new trial of blood pressure lowering in people with “untreated hypertension,” which is said to affect over a billion people worldwide and require lifelong treatment. This trial randomised 21 participants, of whom three dropped out, and it has taken 24 authors to report the results. The primary outcome was “placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks,” and analysis was by intention to treat. Um, hang on. This is the Lancet. Does it even matter what the intervention was when the trial was so miserably underpowered to detect anything clinically meaningful? As it happens, when their 18 participants took a “quadpill” (sic) containing low doses of irbesartan, hydrochlorthiazide, amlodipine, and atenolol, their BP was 100% within target range, whereas on placebo the figure was 33%. Moral: a third of these “patients” didn’t need treatment and the rest would probably have responded to usual stepped-up treatment to lower their blood pressure, if, after full discussion of harms and benefits, they agreed that this was what they wanted.

The BMJ 11 Feb 2017  Vol 356
Post-marketing futility
Germany has come to seem like a beacon of rationality and humanity in a darkening world. Its drug regulatory agency, IQWIG, actually wants to regulate drugs and protect patients. But once a drug is past the GO sign for marketing, the mechanisms for surveillance are as poor as anywhere else. According to the German Medicinal Products Act, all companies initiating a post-marketing study in the German drug market are required by law to register their study. Such studies are essential to detect rare or unexpected events, which could not be picked up in randomised trials of limited size. But the conduct and the results of this surveillance are shrouded in mystery and even commercial secrecy. An investigation using freedom of information requests to three agencies concludes that: “Post-marketing studies are not improving drug safety surveillance. Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are strictly obliged to maintain confidentiality towards the sponsor. High remuneration and strict confidentiality clauses in these studies could influence the physicians’ reporting behaviours of adverse drug reactions.”

Hang on to the ovaries
Premenopausal ovaries matter for more than just fertility and the short term benefits of circulating oestrogen. In the US Nurses’ Health Study, a cohort of 30 117 participants had a hysterectomy for benign disease, and it was found that all cause mortality, coronary heart disease mortality, and deaths from all cancers were significantly decreased when ovarian tissue was conserved compared with when both ovaries were removed. Now there is evidence on an even larger scale, based on linkage of the English Hospital Episode Statistics and the national registration of deaths (Office for National Statistics).  The investigators included 126 005 women between the ages of 35 and 45 who had hysterectomies for benign disease. Of these, 37 098 had their ovaries removed. The oddest finding is that readmission rates for ovarian cancer were higher when both ovaries were removed. I’ll leave you to read the article if you want to know why. The key message is that patients who had ovarian conservation had a significantly lower hazard of all cause mortality compared with those who had bilateral ovarian removal, and also had lower death rates from ischaemic heart disease and cancer.

Plant of the Week: Helleborus x ericsmithii “Winter Moonbeam”

On this horrible dark cold day that I’m writing, I don’t suppose anyone is making the effort to go round the nurseries that specialise in hellebores. This is a pity, as now is the time to buy them, when you can see them in flower. There have never been so many lovely ones, largely due to the efforts of Eric Smith (1917-1986). He was the first to cross Helleborus niger (the Christmas Rose) with Helleborus x sternii (H.argutifolius x lividus). The hybrids used to be called H x nigristern, but I’m glad that they now help to immortalise his name, because all people who create lovely winter flowering plants deserve the gratitude of posterity.

The original “nigristerns” had red stems and mottled foliage with fringed edges, while their flowers were an awkward mixture of pink, white, and green. I guess that it is through careful selection of seedlings that we have now arrived at magnificent vigorous plants, which preserve the beauty of the leaves while bearing flowers of purer colour, ranging from deep purple to clean white. At the same time, new propagation techniques appear to have transformed the malodorous and unrewarding task of splitting plants and then waiting two years for them to come out of their sulk into something that allows the best forms to be sold in profusion at reasonable prices. Put on your coat and scarf and bobble hat and buy some now.