Richard Lehman’s journal review – 1 November 2010

Richard LehmanJAMA  27 Oct 2010  Vol 304
Perhaps the greatest prize in preventive medicine this century will be the discovery of an effective non-surgical intervention to cure obesity. This study doesn’t quite achieve that, but at least it shows that there is still something to be gained from those two old mainstays, diet and exercise. The team from Pittsburgh refused to be put off by the disappointing results of previous trials, and they didn’t cheat either: they selected a difficult population of people with BMIs over 35 – many were black with BMIs over 40. If anything, their methods were too rigorous, including two high-radiation CT scans to determine abdominal and hepatic fat. They provided free liquid feeds to participants who consumed a balanced diet of fat, carbohydrate and protein. Those randomised to diet plus exercise in the first six months lost a bit more weight than those randomised to diet alone: but the latter group caught up quickly when they started exercising, and at one year everybody was lighter by about 10kg and showed improvements in waist circumference, abdominal fat, hepatic fat, blood pressure and insulin resistance.

1803  The next trial was somewhat similar though it was designed to see if providing free prepared meals was an important part of the intervention, and whether face-to-face encouragement would be more successful than telephone encouragement. Over 400 women were recruited, with BMIs between 25 and 40, and the study ran for 2 years. Those provided with free meals and face-to-face counselling achieved a mean weight loss of 7.4kg, while the telephone group were about a kilo less successful.

1821   Clopidogrel continues to dog our steps. Clop-clop: hardly a week goes by without some confusing difference of messages in new studies. Here a meta-analysis of 9 studies reaches the conclusion that the effect of clopidogrel is reduced by the carriage of CYP2C19 reduced-function alleles, so that the more of these you carry, the more likely you are to suffer stent thrombosis and major cardiovascular adverse events following percutaneous coronary intervention. But the PLATO data from a couple of weeks ago seemed to tell the opposite story, and now data from the CURE and ACTIVE trials (see NEJM) back that up: according to these latest data, it doesn’t matter at all what genotype you carry, you will still benefit from clopidogrel. I await some explanation from my learned friends.

NEJM  28 Oct 2010  Vol 363
1693   While the application of genomics to most of medicine proceeds by fits and starts, the life-and-death struggle of individuals against cancer lends urgency to the developing science of tumour genomics, well illustrated in this week’s NEJM. Various types of tumour are bunched together under the label non-small-cell lung cancer, but researchers have now identified a subset of tumours which express the genes EML4 and ALK, the latter standing for anaplastic lymphoma kinase. In fact these are mostly adenocarcinomas arising in non-smokers. There is an orally available ALK tyrosine kinase inhibitor called crizotinib which was tested for such tumours here in an early-phase trial. The results at six months were very promising – most tumours were arrested or shrank. But alas, a Japanese study of such tumours shows that they have several ways of developing resistance to ALK inhibitors.

1704   Here’s the study I mentioned which seems to discredit the idea that the effect of clopidogrel is influenced to any clinically significant extent by CYP2C19 reduced-function alleles. The subjects in the CURE trial were randomised to clopidogrel for acute coronary syndromes labelled unstable angina, whereas those in the ACTIVE trial had atrial fibrillation. These yielded over 5000 patients who were genotyped for the three loss-of-function CYP alleles. It’s striking that this made no difference to outcomes in either context, and frustrating that the journal hasn’t commissioned an editorial from someone able to account for this.

1715   A trial called TALC will probably influence the management of adults with uncontrolled asthma right away, though the authors are careful to discourage that until the results of the bigger, longer BASALT study come through: “we evaluated only a small number of patients, with no treatment lasting longer than 14 weeks. Since we could not examine either the rate of asthma exacerbations or long-term safety issues, our findings cannot be considered clinically directive.” Using a nice cross-over design to squeeze as much information as possible from their 210 patients, they demonstrated that tiotropium bromide is as effective at improving morning peak flow rate as a long acting beta-agonist (salmeterol) and more effective than doubling the dose of inhaled glucocorticoid.

1740   List the evidence-based interventions for recurrent miscarriage. Yes, that will do nicely – there aren’t any. Even the use of aspirin with or without unfractionated heparin in women who are positive for antiphospholipid antibodies on two or more tests is not of proven benefit. In fact there is now some doubt about the strength of the association between recurrent miscarriage and the presence of antiphospholipid antibodies, discussed by Prof Ware Branch of Salt Lake City both here and in this week’s Lancet. Similarly with other prothrombotic markers, such as Leiden V. Uterine anomalies are best left alone. This is an excellent review which holds out considerable hope for couples with recurrent miscarriage – if they simply keep trying, and don’t waste their money on private clinics who will fleece them with unnecessary investigations and interventions.

Lancet  30 Oct 2010  Vol 376
1467   Millions of people worldwide carry a virus which will one day kill them – hepatitis C. Many more millions carry the same virus, but will remain blissfully unaware of it throughout their normal lifespans and will die of something else. So I think this is a virus which we will be living with for a long time to come, even though we will probably be able to cure hepatitis C within the next decade. At the moment the standard treatment is pegylated interferon alfa by injection with oral ribavirin, but this Antipodean study run by Roche Palo Alto used a combination of two oral agents which don’t yet have names: one a protease inhibitor and the other a nucleoside analogue polymerase inhibitor. I won’t try to explain: for that you are best to go to the very upbeat editorial on p.1441.

1498   Ever since I learnt of its existence about 20 years ago, I’ve been looking out for a good clear account of antiphospholipid syndrome. This isn’t it, though it contains plenty of information. The review might have done well to start with a definition, and a clearer explanation of the three laboratory tests – lupus anticoagulant, anticardiolipin antibody and anti-β2-glycoprotein 1 antibody. Somewhere here you’ll find just about all the evidence there is about treating the condition(s) and some speculation on what to try next.

BMJ  30 Oct 2010  Vol 341
926   Antenatal screening is largely a matter of service organisation and people doing what they are told. If we were serious about screening for sickle cell disease and thalassaemia in newly pregnant women, we wouldn’t mess about: we would just go ahead and take the blood while muttering some sort of explanation. In this trial conducted in practices with high proportions of ethnic minority groups, uptake of early screening by explanation and consent was less than 30% in the two intervention protocols; it was 2% in the midwife usual care group. However, I have no idea how important this issue is, since neither the paper nor the editorial (billed as “by Shakespeare” – my gracious GP colleague Judy rather The Bard) gives a national figure for the number of affected babies or terminations.

927   As soon as Priestley described his discovery of dephlogisticated air, people as well as mice wanted to enjoy its beneficial effects, and one Dr Thomas Beddoes even went so far as to set up a Pneumatic Institution to try the effect of this and various other gases on suggestible ladies in Bristol. Dephlogisticated air supported life and encouraged combustion: it also generated acidity and so became known as oxygen. It remains dangerous stuff, especially when used in cardiac ischaemia and chronic obstructive airways disease, as demonstrated here by the paramedics of Tasmania. Whenever they picked up an acutely breathless patient with a possible history of COPD, they gave oxygen either in the conventional form of continuous high flow during transfer to hospital, or according to a titration schedule guided by pulse oximetry. The death rate from respiratory failure was much lower in the latter group.

928   As the political pendulum of opioid addiction swings towards a “make the junkies break their habit” populist phase, spare a thought for what methadone cessation actually does to people who have been using it as substitution therapy. This study of the UK GP Research Database finds an 8-9 fold increase in mortality in the month after discontinuation.

930   Managing diabetic retinopathy is an excellent contribution to the BMJ Clinical Review series, which I read with care since retinopathy is one of the “microvascular end-points” that are often poorly defined and bunched together in interventional studies and systematic reviews of diabetes treatments. The authors here lay out the evidence with great clarity, though their prevalence and progression figures may not reflect the current situation, as they date from 1995. I particularly warm to their statement that perfect control is never attainable in type 1 diabetes, and rarely in type 2. Nor is it always attainable for blood pressure either, but that’s where the maximal preventive benefit lies.

Arch Int Med  25 Oct 2010  Vol 170
1710   This useful systematic review takes a look at the evidence concerning the risk of recurrence following a first episode of venous thromboembolism caused by a transient risk factor. The figures derived from 15 prospective studies make interesting reading: the overall risk is 3.3% in the first year and exactly the same in the second year. But if the VTE followed a surgical procedure, the figure is much lower at 0.7% per year. Conversely, if no precipitating factor could be found, the risk was much higher, at 7.4%.

1752   Inserting scoping tubes into the orifices of the gastrointestinal tract is an ever-increasing activity, and not entirely without its hazards. This paper tries to quantify the risk of hospitalisation following upper GI endoscopy and colonoscopy using a novel automated system. Although such complications occur at just under 1% following these procedures, the cost of such admissions is calculated to add another $48 to each procedure.

Plant of the Week: Tricyrtis formosana

The toad lilies are lovely, unobtrusive plants to enjoy right at the end of the season, provided you have a reasonably damp and shady spot to put them. I have lost count of the number we have bought and lost to drought and slugs, but we carry on. This is one of the easier ones, which can even get a bit invasive via its spreading roots (or stolons, hence the name of a subgroup, T formosana var. stolonifera). Like all the toad-lilies, the Formosan has six-lobed petals of curious shape and beauty, spotted like the snakes in A Midsummer Night’s Dream.