Richard Lehman’s journal review—1 October 2012

Richard LehmanArch Intern Med  24 Sep 2012  Vol 172

Of Exercise I sing, and that benignant sweat
Which from six thousand diabetic brows
Exudes. My pen, Hygeia, speed! To save
That honey-urined tribe from mortal pains
Which Indolence doth breed, and glut of food:
That to the treadmill they may go, or healthful jog,
Or bicycle with ever-turning wheel;
These strivings, Muse, assist me to exhort,
That to the height of this great Argument
I may assert eternal Exercise:
For sloth in diabetes hastens death.

I beg your pardon: I was just trying to think of an EPIC way to convey the message of this paper about the mortality benefit of exercise in a cohort of 5859 diabetic individuals followed up from 1992 onwards in the European Prospective Investigation Into Cancer and Nutrition (aka EPIC). I know there’s confounding and reverse causality to be considered, but the burden of all such studies is always the same: even small amounts of regular exercise buy large amounts of added life.

1301    Nothing else in diabetes is as straightforward as the benefit of exercise: blood pressure control in type 2 DM for example, is a subject of such intellectual complexity that I sometimes think only Rod Hayward really understands it. The message of this systematic review and meta-analysis seems to be fairly clear: if you set a target BP with an upper limit of 130/80 rather than 140-160/85-100, you will reduce stroke but have no significant effect on total mortality or myocardial infarction. That may be all that a jobbing clinician needs to remember, but if you drill down just a little deeper, things get a good deal more complex. There is no simple—or even complicated—formula that can just give you a read out of numbers needed to treat for risk reduction in type 2 diabetes with hypertension. You must always consider the totality of cardiovascular risk in the individual patient. If you really want to engage with this, combine this study’s findings with the classic Timbie, Hayward and Vijan modelling paper from 2010.

JAMA  26 Sep 2012  Vol 308
1221  This RCT forms a footnote to the systematic review of corticosteroids following tonsillectomy which appeared in the BMJ three weeks ago. It doesn’t really add anything new: there was slightly more bleeding in the steroid group but it did not reach statistical significance.

1227   Total knee replacement is a safe and highly effective procedure for most patients, but in the UK it is being rationed (again) and in the USA it is sometimes cited as an example of supply-led demand. I rather doubt it: it’s a major operation and most people undergo it with reluctance and foreboding, having tried the various ineffectual alternatives for months or years. The volume curve shown in this paper for this procedure in the Medicare population is very much what you would expect: a steady climb followed by a wobbly plateau. The NHS curve is probably similar, but from this year on it will dip, while the same patients hobble round to the private hospital and hand over their savings to have the same procedure done by the same orthopaedic surgeons who are forbidden to fill their NHS lists.

Interventional cardiologists with itchy fingers will all be citing the FAME study (see NEJM two weeks ago) as a reason to put wires in coronary arteries to measure fractional flow reserve (FFR) in stable coronary artery disease. I promised at the time that I wouldn’t comment further on something so far removed from my own field of practice. Here, however, is a technique for measuring FFR without an invasive procedure, unless you count a hefty dose of ionizing radiation as invasive. It is our old friend coronary computed tomographic (CT) angiography with some extra computing thrown in. In this multinational study, 252 patients with stable CAD underwent both CT scanning and invasive FFR measurement with adenosine stimulation. So this is a nice example of a diagnostic study with a simple gold standard: you can plug the figures into your 2×2 table and come up with specificity (73%), sensitivity (90%) and all the rest. Or you can construct a receiver operator curve (AUC, 0.81). Either way, CT derived FFR doesn’t quite cut the mustard. Further refinement might give us more accuracy, but for now, I struggle to think of a clinical use for this imaging modality. People with stable CAD should keep taking their tablets and try to avoid cardiologists with itchy fingers or shiny new CT machines.

1246   How to use an article reporting a multiple treatment comparison meta-analysis is a very good paper written by all the right people, and it describes all the pitfalls from a good practical clinical perspective. But at the end of the day, all you can derive from such comparisons is weak evidence prone to a range of biases. What we need are lots of good head to head comparisons of common interventions in large typical populations. Ben Goldacre cries out for these in his great new book, Bad Pharma, and describes how they could be done easily and cheaply using randomized prescribing in UK general practice. Come on, university departments of primary care: drop what you’re doing and let’s have a programme of coordinated comparative effectiveness research which can deliver the information that clinicians really need for shared decision making with patients.

NEJM  27 Sep 2012  Vol 367
1187   Enzalutamide is a drug you will need to get used to. Before long, every patient with treatment-resistant prostate cancer will be taking it. Nearly half a year of added survival without nasty adverse effects is just the thing we have been looking for: at least it’s the thing I have been looking for on behalf of a friend with castration-resistant prostate cancer, until he died in May. The AFFIRM trial is just your typical pharma run study, ended early because of clear benefit: fewer than ten patients from each of 156 sites in 15 countries, authors with lists of conflicting interests as long as your arm, etc, etc—but this doesn’t alter the validity of the editorial title: Enzalutamide—A Major Advance in the Treatment of Metastatic Prostate Cancer. That editorial is also the best place to go for an understanding of why that should be.

1196   With tiotropium in asthma poorly controlled with standard combination therapy we’re back into the murky world of borderline benefit and special pleading. Boehringer Ingelheim and Pfizer ran two good lengthy trials of their new soft-mist delivery Respimat system for tiotropium versus placebo in adults with “poorly controlled” asthma already taking long-acting inhaled bronchodilators and inhaled corticosteroids. Mean time to first “severe” exacerbation was 226 days in the control groups and 286 days in the active group. A less than rapturous editorial looks at the detail.

1237   I dipped into this week’s Current Concepts review article out of mild curiosity, and was surprised by what I learnt. “Cases of acute hepatitis E account for a large proportion of cases of acute liver disease in developing countries, with smaller (although unknown) proportions in Europe and the United States.” Gosh. It’s a zoonosis and you can get it from undercooked pork products, wild game and shellfish. PCR tests of most shop-sold pâté sold in Europe show traces of hep E viral DNA. It comes from the liver: may it go to the liver. Blimey, no more gastronomy for me then. It can also be a pig to diagnose, with no standardization of human serological tests.

Lancet  29 Sep 2012  Vol 380
This week’s Lancet is largely taken up with global surveys of maternal, newborn, and child health. The global under-5 mortality rate has dropped by 41% and this fall is accelerating, especially in sub-Saharan Africa. But Richard Horton is displeased; “a shocking pattern of failure” must be seen and treated with large doses of personal indignation, The Lancet’s unfailing remedy for every global ill. What he means is that in some countries (actually just two), under-5 mortality has risen. Not surprisingly, the countries that fare worst are those that the West either ignores completely or fights its proxy wars in. Worthy cause for indignation indeed, but that shouldn’t preclude massive celebration—plus a massive campaign for global contraception if we want progress to continue.

BMJ  29 Sep 2012  Vol 345
In the USA, they call it “clinical Gestalt,” but I’m pleased to see that in the UK we can still call it gut feeling. This week I’m facing 12 hours of acute clinical triage, a lot of it involving children with infections, and just now the feeling in my guts is so-so. Every now and again you get one that worries you: this paper states that about one in 200 children seen in primary care has a serious condition that is easily missed, but in out-of-hours care it’s much more than that. One in 50 perhaps—someone needs to do the study. This one was conducted in Flanders, but the paper also has two Oxford authors who have done a great deal of good work in this area. Rightly, the factor that caused the most concern in doctors was parental anxiety.

Obesity in children is a growing problem on a global scale, although in the UK it is actually falling. Is that due to some wonderful fix discovered by the last government and rolled out by a skilled cadre of public health physicians and community paediatricians? Well no, because no such wonderful fix exists. This systematic review of the better trials shows that interventions to promote physical activity in children have a negligible effect on physical activity in children, which is overwhelmingly what they do of their own accord. Now if kids were let loose on all the policy documents, local plans, and academic papers ever printed on this subject, and told to tear them up into the tiniest pieces they can, there would be an enormous surge in paediatric exercise levels and enough pulp to save an entire forest.

Some kids, on the other hand, don’t put on enough weight. In babies and toddlers we used to call this failure to thrive, but it seems that the term “weight faltering” is taking over. Here’s a rather dry run through the evidence, which suggests that we should be more relaxed about it and above all that we shouldn’t immediately suspect parental neglect.

My Oxford colleague Matthew Thompson appears as second author in three papers in this week’s BMJ; something perhaps for the Guinness Book of Records. This one is an Uncertainties Page piece (four pages long) on the factors which influence prognosis in children with acute cough and respiratory infection in primary care. It’s a good topic, because RTIs are the commonest reason for GPs to see pre-school children and also the commonest reason for prescribing them antibiotics. The reviewers don’t find much useful science to guide decision-making in this area, but at least that’s a good starting point for designing some.

Plant of the Week: Lavatera “Barnsley”
In the 1980s, everybody had this shrub in their gardens, covered in pale pink flowers with a dark boss from July to October. It even achieved a reluctant article in the Royal Horticultural Society’s monthly guide to what proper people grow, The Garden. That seems to have spelt its doom: ever since, it has grown less common, and I begin to miss it.

But I don’t think I would be willing to give scarce garden space to this big straggly shrub again unless someone produced a new range of hybrids. So why don’t they? Lavatera is just a kind of mallow, closely related to the hollyhock. The hollyhocks in England this year have been terrific, and they come in the most ravishingly subtle colours, single or double. But you never know if the plants are going to last for one year or three: seldom more than that. Lavateras last for ten, and it should not be beyond the wit of a molecular hybridist to get some hollyhock genes into these woody mallows and produce shrubs with abundant flowers ranging from greenish white to nearly black with all the softest colours between—pale brownish pink, apricot, blackcurrant purple—to decorate our gardens for months on end. You could cut branches to bring them into the house—and if you do that with a hollyhock, you are likely to discover that the flowers last well and give out a delicious faint pervasive fragrance.