Richard Lehman’s journal review—5 June 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  1 June 2017  Vol 376
Minocycline to prevent demyelination?
Over a couple of decades, the tetracycline antibiotic minocycline has shown glimmers of promise in the treatment of multiple sclerosis, because it crosses the blood-brain barrier and exerts anti-inflammatory effects, which have nothing to do with its action as an antibiotic. This Canadian trial should really have settled the question of whether it can usefully influence the very earliest clinical stage of MS, which is the transition from the first episode of symptomatic demyelination to the next. Tantalisingly, it falls just short. The 72 patients who were given minocycline after a first demyelinating event showed a 34% conversion to multiple sclerosis by six months, whereas in the 70 who got placebo the rate was 61%. But as time went on, the difference became smaller, so that it was no longer statistically significant by two years. Something was happening, but this trial proved underpowered to show the true effect size over time. So the use of minocycline to prevent progression to MS remains an experimental idea rather than a breakthrough.

Capecitabine for residual breast cancer
When I first started commenting on oncology trials each week in the late 1990s, I was inclined to be generous and regard each small success as part of an incremental process: helping to conquer one cancer at a time, by means of one advance at a time. Some cancer trials are still like that, i.e. designed to help patients, rather than bleed them dry with false promises of marginal benefit. I think this trial is a virtuous example, although I will leave the final judgment to my better informed friends Bishal Gyawali and Vinay Prasad. It was carried out with non-industry funding in Japan and South Korea, which is nice to see. The aim was to see if adding capecitabine to standard treatments might improve the otherwise poor prognosis of patients with residual invasive HER2–negative breast cancer after triple chemotherapy. At five years, there was a 4.6% overall survival advantage in the group given capecitabine, at the expense of a 73.4% rate of hand-foot syndrome. Someone needs to design a decision aid for patients faced with this choice.

Pardon me, it’s ANGPTL3
Ooh, it’s drug developers  playing with mice! They found a gene locus common to mice and men called ANGPTL3. This governs levels of low density lipid (LDL) cholesterol and triglycerides, and I won’t try and tell you which way round it works, as I’m bound to get it wrong by the time we’ve gone through loss of function variants, angiopoietin-like 3, antisense oligonucleotides, and messenger RNA. Suffice to say that Ionis Pharmaceuticals did the mouse experiments and showed that their antisense oligonucleotide reduces hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and LDL cholesterol. They then tried various doses in 44 humans, with a similar effect on these markers.

Regeneron Pharmaceuticals are targeting the same process but with a monoclonal antibody called evinacumab, and they have reached a similar stage. Now you will have to try and contain your excitement for about 10 years to see if either or both of these agents can safely reduce real events in lots of real people.

JAMA  Intern Med  June 2017  Vol 177
Avoiding readmission may not save money
As a person who has a little job with Cochrane UK, I shouldn’t say this too loudly, but I’m beginning to wonder if most meta-analyses of complex interventions are a waste of time. What the world needs to know about are successful models of care that are clearly defined, generalisable, and which work over many years. What you usually get from an attempted meta-analysis is a muddy emulsion of different interventions, which together don’t show much effect and leave the reviewers calling for better studies. I’m not singling out this one for special criticism.

It’s about the cost effectiveness of quality improvement initiatives to reduce hospital readmission. They did the best job they could. Here’s the conclusion: “Multicomponent QI interventions can be effective at reducing readmissions relative to the status quo, but net costs vary. Interventions that engage general populations of patients and their caregivers may offer greater value to the health system, but the implications for patients and caregivers are unknown.”

Ann Intern Med  30 May 2017  Vol 166
Cheap old drugs for rheumatoid
Just to remind you: back in 2013 the NEJM  published the RACAT (Rheumatoid Arthritis Comparison of Active Therapies) trial, which showed that old fashioned drugs in triple combination worked as well as etanercept-methotrexate in active rheumatoid arthritis. Here is the cost effectiveness analysis. The unsurprising conclusion is that initiating “biologic” treatment without trying triple therapy first will waste money for little benefit.

The Lancet  3 June 2017  Vol 389
Aflibercept for diabetic eyes
Diabetic proliferative retinopathy is usually treated with panretinal laser photocoagulation (PRP), which reduces the risk of severe visual loss by 50%. But if you do it too often, it can result in visual acuity below the driving standard, restricted visual fields that preclude driving, night vision difficulties, loss of colour vision and reduced contrast sensitivity, and increased macular oedema. So it would be great to have an alternative treatment, and this trial used intravitreal aflibercept instead. “What’s that?” I hear you ask. Flipping heck, aflibercept is an anti-vascular endothelial growth factor (anti-VEGF) therapeutic agent: you should know that by now. It’s the latest and most expensive. The others are ranibizumab and bevacizumab. The CLARITY phase 2b trial shows that over 12 months, it gave better results than standard PRP treatment. This was not an industry funded trial, but it’s a pity that they chose aflibercept as we’ve learnt since that ranibizumab is similarly effective for diabetic retinopathy; and there’s no reason to believe that bevacizumab, which is cheaper by several orders, wouldn’t work as well. Flabbergastingly priced aflibercept may not be the best choice after all: some head to head trials with bevacizumab, please.

From a bad place on to death
“Adversity-related injury” is a new term to me: in this study it refers to self-inflicted, drug related, alcohol related, or violent injury, and it affects 4% of 10-19 year-olds in Britain. Their risk of death in the decade after hospital discharge is twice as high as that of adolescents admitted to hospitals for accident related injury. This nationwide study, funded by the UK Department of Health, delves into the causes of these deaths. Not surprisingly, they are mostly due to suicide, violence, or alcohol/drug related causes.

Ketamine doesn’t prevent post-op distress
Ketamine is enjoying a new medical vogue as the water of Lethe, which takes away the memory of pain. It seems very reasonable to have tested the hypothesis that small doses of this anaesthetic agent given during surgery might reduce post-operative delirium. But it had rather the opposite effect: there were more postoperative hallucinations and nightmares with increasing ketamine doses compared with placebo. This was an international trial called PODCAST, and pain features in the title of the paper but is never mentioned as an outcome in the abstract. For that you have to go to the text and tables of the article, where pain is reported as a secondary outcome. Having had intraoperative ketamine made little difference at any point.

The BMJ 3 June 2017 Vol 357
ADHD and maternal antidepressants
If you put “prenatal AND antidepressant*” into a PubMed search, you will get 483 hits, some of them detailing new study protocols and others calling for a halt to the flood of observational studies. I think we can safely conclude that the use of antidepressants in pregnant women is strongly associated with a diagnosis of Association-Dredging Hyperactivity Disorder. The trouble is that once you have dredged up an association you leave people with an impression of causality, which can’t be dispelled or confirmed. It’s rather like the label of Attention Deficit-Hyperactivity Disorder in children. Once they have it, it sticks to them and often means that they are put on amphetamine-like drugs for several years of critical brain development. I would not wish that fate on journal authors with Association-Dredging Hyperactivity Disorder: it might make them worse, and leave me with even more papers to read. This one, by the way, is a very sound reanalysis of population data from Hong Kong and reaches the conclusion that “the association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication of antidepressants. If there is a causal association, the size of the effect is probably smaller than that reported previously.”

Causal ignorance about birth defects
Proving causality in medicine is actually far more difficult than most people realise. Often it is impossible, especially in relation to individuals rather than populations. Here’s an important paper on the etiology (sic) and clinical presentation of birth defects. You will note that while all US journals convert British spellings to American, The BMJ does not return the favor/favour. But let’s not call the whole thing off. Here is the summary of a study of 5504 birth defects in the population of Utah: “Definite cause was assigned in 20.2% of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects.” Now the numbers here don’t add up: look instead at the table in the paper, in which chromosomal or genetic conditions together account for 19.1%, which is the correct figure. The take home message is that we don’t know what causes four out of five birth defects.

Plant of the Week: Geranium pratense “Gerald’s Drive”
It’s quite rare for a native perennial plant to be a good thing in a garden. Take bindweed: it’s beautiful as a roadside plant, tumbling over grass verges in its pink form, or climbing into hedges and bestowing big white trumpet flowers on them in late summer. Yet you would be mad to want it in your garden, any more than you would want buttercups or dandelions.

The hardy geranium G pratense is a native perennial, and its name refers to the profusely flowered meadows, which have now largely disappeared from England. I have never myself seen it flowering in a field, but great blue patches of it often decorate the road verges of the Cotswolds. If you bring it into your garden, you can expect it to thrive forever, and produce numerous offspring. But unlike bindweed, it has no desire to take over the deep places of your soil in perpetuity. If you have no room for its progeny, you can pull them up with ease and put them in the compost bin.

I would, however, recommend that you give them a chance to flower first, so you can keep the best. Seedlings of the meadow geranium have produced all sorts of lovely varieties, which you can buy under various names in plant nurseries. But you will never find one called “Gerald’s Drive,” though it is one of the very best, and it did come from a plant nursery. Ours is the only copy. We were about to leave the nursery, run by Gerald Sinclair, when we noticed a particularly lovely pale blue geranium growing on his drive. He let us dig it up and it is still thriving, 20 years later. He, alas, has gone into retirement, but we remember him fondly whenever we look at this plant.