Richard Lehman’s journal reviews—13 June 2016

richard_lehmanNEJM 9 Jun 2016 Vol 374
All sorts of AML
2209 Ernest Rutherford (1871-1937), New Zealand’s greatest son, said that physics is the only science, and the rest is just stamp collecting. Nowadays physics seems largely about making stuff up, so I feel safer with the stamp collectors. And what wonderful stamps they are finding every day! When you were a student with your medical school stamp album, there was just one Penny Black, called Acute Myeloid Leukaemia (AML). Now they’ve looked at the watermarks and all that sort of thing and it turns out that there are 76 types of Penny Black or AML. And this, of course, matters a great deal if you happen to have one of them. Quarks, wormholes, and superstrings will or will not exist forever, whether or not you are alive, but if your AML doesn’t get the right treatment you will soon cease to puzzle about such things and become part of the unknowable. Most people wish to postpone this. To get AML is a misfortune, but to get AML with chromatin–spliceosome and TP53–aneuploidy is doubly so. You have a bad prognosis, and at the moment there is not a lot that can be done about it. In ten years’ time, there might be. Let’s hope that in the meantime, the biggest obstacle to progress in oncology—completely unaffordable tests and treatments—will have been sorted. An 1840 Penny Black will set you back about £2500 at current prices. That might buy you a couple of weeks’ worth of combined chemo and monoclonal antibody treatment. So I read papers like this about genuinely huge advances in our understanding of cancer with mixed feelings: will these patients genuinely benefit or will they become victims of the current “your money or your life” system of oncology drug development?

COPD puffer puffed
2222 When a drug company runs a trial on a large number of people across a large number of sites, you can be reasonably certain that their intention will be to show a small effect and/or spread news of their product to as many doctors as possible. Chronic obstructive pulmonary disease (COPD) is very common, and is a very lucrative market for drugs that patients have to take on trust, since they will personally never know if they have fewer exacerbations than they otherwise would have. Most people with COPD currently take salmeterol-fluticasone inhalers, often with tiotropium thrown in. If you’re a GP, you can easily check how many patients in your practice are on this combination. Twenty? Forty? A hundred? In this Novartis trial (FLAME), 3362 patients were enrolled at 356 centres in 43 countries, i.e. 9-10 per location. The logistics don’t make scientific sense: you could easily have done the whole trial in 10 major chest centres. Participants were randomised to get salmeterol-fluticasone or the new Novartis combination of indacaterol–glycopyrronium for 52 weeks. The new inhaler won by 0.44 of an exacerbation a year per patient. Short term adverse events were similar. I wish there had been a placebo group, but it seems that every COPD patient now has to enter this belief system. It’s time somebody did a shared decision aid based on absolute benefit in the short and the long term for each outcome, and its distribution.

A Hill of salt
OL The salt reducers have been given a sounding board in the NEJM, entitled Dietary Sodium and Cardiovascular Disease Risk—Measurement Matters. They argue from Bradford Hill’s principles for determining whether an observed association is causal: strength, consistency, specificity, temporality, biologic gradient, plausibility, coherence, experiment, and analogy. So far, so good: you may remember that Hill was so strict with the use of observational data that he advised Richard Doll not to submit his original paper on smoking and lung cancer for lack of rigour. But every section of the article consists of special pleading for the linear relationship between salt and cardiovascular events, mediated by blood pressure. I’m no Bradford Hill, but I just don’t think this argument is sustainable: the better the measurement methods, the less plausible it gets.

JAMA 7 Jun 2016 Vol 315
Wobbles in the US fat plateau
2284 Obesity in American adults has just about plateaued. OK, it still isn’t an attractive sight: a wobbling belly of a plateau with 35% of men and 40.4% of women obese by the criterion of BMI>30. And women are still tending to get a little fatter. This is an approximate summary of data obtained from the National Health and Nutrition Examination Survey (NHANES) over the nine years preceding 2014. This cannot be good, yet it isn’t having the dire effects that many have predicted: type 2 diabetes is on a slight wane, and cardiovascular disease continues to drop. Eating too much seems to be the chief comfort of many Americans. Mind you, it can have its advantages. In a traditional restaurant on the Connecticut coast, I ordered the evening special, which consisted of a six inch high mountain of steamed clams on a huge plate, surmounted by two lobsters with a large bowl of melted butter ($33). With a generous side order of fries and a large beer or two, I spent a very pleasant hour with marine juices trickling down my forearms. Fortunately, I had a son there to help me.

Obesity in US kids
2292 But what about the kids? (My sons are no longer kids) Let me just give you the summary: “In this nationally representative study of US children and adolescents aged 2 to 19 years, the prevalence of obesity in 2011-2014 was 17.0% and extreme obesity was 5.8%. Between 1988-1994 and 2013-2014, the prevalence of obesity increased until 2003-2004 and then decreased in children aged 2 to 5 years, increased until 2007-2008 and then leveled off in children aged 6 to 11 years, and increased among adolescents aged 12 to 19 years.”

Early GA & cognitive outcomes
2312 Had general anaesthesia (GA) in human babies started off with animal experiments, it might never have caught on, since exposure of young mammals to commonly used anaesthetics causes neurotoxicity, including impaired neurocognitive function and abnormal behaviour. Fortunately, that doesn’t seem to apply to young humans exposed to a single administration of GA in their first 36 months. Here’s a neat long term study of 105 sibling pairs in which one received GA for inguinal hernia surgery before the age of 3 (median duration 80 minutes). When assessed at the age of 10-11, no statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behaviour.

JAMA Intern Med Jun 2016
Outcome measures matter
OL You know you’re old when you meet the age criteria of a hospital mobilisation trial for people aged 65 and over. At this age you don’t have a life any more, only something called “activities of daily living” (ADL). You also have this thing called “community mobility”—all to do with shopping and having tea with other old people, I guess. In this trial, US veterans of this venerable age who were admitted to Birmingham (Alabama) Veterans’ Hospital were randomised to receive a mobility intervention twice a day or usual care. After discharge there was no difference between groups in ADL score. But the ones in the intervention group had greater community mobility, as judged by the distance they moved outside home. Have to stop now. I’ve just run out of denture fixative and I’m going to pop by at Alf and Violet’s for a nice cup of tea. Activities like this are apparently associated with a lower risk of death, nursing home admission, and functional decline. So that’s something to look forward to.

Overtreating diabetes
OL It’s five and a half years since I tagged along with John Yudkin on a short, life changing visit to Yale to talk diabetes with Harlan Krumholz. On that occasion I first met Joe Ross and Kasia Lipska, and the following year I met Victor Montori and Nilay Shah. Together they comprise most of the authors on this new paper assessing how many out of 31 542 people with type 2 diabetes on an insurance database were likely to be receiving too much treatment, and what effect this had on rates of hypoglycaemia. They conclude that over 20% of these patients fall into the overtreated category, and that this nearly doubles their risk of hypos. You may say I like this study because I think that these friends are among the coolest people in medicine. This is true. It is also an important study. Someone needs to look at the UK figures.

Lancet 11 Jun 2016 Vol 387
Gymslip mum shock horror (not)
OL It’s rather old news by now, but British teenage pregnancy rates, which used to be among the highest in the developed world, have come down dramatically since their peak in 1998. The authors of this study conclude that “A sustained, multifaceted policy intervention involving health and education agencies, alongside other social and educational changes, has probably contributed to a substantial and accelerating decline in conceptions in women younger than 18 years in England since the late 1990s.” Quite possibly, though, there is no way of knowing. If that is true, then Figure 1 of this open access paper illustrates that you cannot expect such changes to be evident in the course of a single electoral cycle. The Teenage Pregnancy Strategy was published in 2000, by which time conception rates were already beginning to fall. Conceptions fell at the same slow rate until 2008, by which time they were at the same level as 1994, at around 40 per 1000 women aged 15-17. But since 2008 the rate has fallen dramatically, and by now it must be about half that if the linear trend has continued downward since 2014. Note to the Department of Health and public health physicians: if you set up a strategy for something, be consistent in adopting it and wait for 15 years before judging its success. And then be cautious about taking the credit, unless you have set up a population control. In fact, exactly the same drop in teenage pregnancy has happened across the US.

Fundamental choices
OL Haemorrhoids are swollen veins, and you can leave them alone or treat them with rubber bands. That is about as far as my understanding stretches. It had never occurred to me that where there are veins there must be an artery to feed them, and that one way to treat piles might be to ligate the haemorrhoidal artery. Apparently this is a procedure that has caught on with proctologists. The British HubBLe trial sought to compare the rubber bands with arterial ligation in people with second and third degree haemorrhoids. They found that ligation is more expensive, has more complications, and is more painful. The humble rubber band is an article of great domestic value, although it has uses that you should not try out at home.

The BMJ 11 Jun 2016 Vol 353
For six years, I haven’t been responsible for adding to anyone’s list of regular medications. But before that time, my sins were grievous. It’s only since I retired from daily general practice that I fully realised how much easier it is to start a medicine than to stop it; and also that most times when I referred a patient to a specialist, I was putting myself in the position of having to prescribe another drug afterwards, whether or not I believed it was necessary. John Yudkin came up with his Ten Commandments for a New Therapeutics three years ago, and they appeared in a modified and annotated form last October in the BJGP. Probably the most important rules are never to start a new long term treatment before you have considered what you might stop, and always try to share these decisions fully with patients. Here is a wonderfully practical and insightful analysis piece on how to withdraw medication from overmedicated older people. I do wish it was open access: it’s a lot more important than the Lancet paper about piles and rubber bands.

Plant of the Week: Lupinus arboreus

I’ve written about this shrub several times before, and it seems strange to choose it again when mid-June offers such a profusion of delectable alternatives. But it is simply the most spectacular plant in our garden at present. It is a vast mass of creamy yellow spikes, lightening up a space three metres across and filling it with a wonderful scent.

I’m surprised to encounter seasoned gardeners who have never heard of the tree lupin. It is about the easiest thing to grow. Ordinary lupins rarely last more than a year or two and attract every gastropod from miles around: I counted 11 slugs and snails on one of our border lupins the night before last. The tree lupin is relatively immune from attack, and ours has lived for five years so far. That is reasonably good going for this rather transient shrub. I cut it back fairly savagely once the flowers are turning to seed, and it quickly sprouts back with lots of dainty fingers of leaf.

It’s really odd that you don’t see this plant for sale everywhere. When you do find it, it’s likely to be cheap, as it’s very easy to propagate. Although its native habitat is in poor soil along the northwestern coast of America, it seems to appreciate good feeding and a bit of shelter. It needs a bit of discipline and staking too, as its natural habit is scruffy and its branches are brittle. Always buy it—if you can find it—while it is in flower, and go for a good clear pale yellow. In its more northerly natural habitat, lupin trees bear greyish washy blue flowers, and they are absolutely worthless in the garden.

And now for my top tip: sprinkle nigella seed (love-in-a-mist) around the base of your yellow flowered tree lupin, which has a natural tendency to produce low hanging branches. The beautiful lacy blue nigella flowers will intermingle with their soft cream yellow candles: exquisite.