Richard Lehman’s journal blog, 12 July 2010

Richard LehmanJAMA 7 July 2010 Vol 304
Glucosamine is the doctor’s best friend. It doesn’t do anything, but people believe it might, and so if you have trouble treating their joint symptoms you can always say “have you tried glucosamine?”. Note that you are not obliged to lie: the most you have to say is that it seems to work for some people. In this Norwegian double-blinded trial for chronic low back pain and degenerative lumbar osteoarthritis it was as good as placebo, with slightly fewer adverse effects.

61 As part of the ongoing upturning of the Sacred Truths of Diabetes, this analysis of data from the INVEST study shows that tight control of blood pressure in diabetic patients with coronary artery disease does not improve outcomes. And so another unwarranted extrapolation from UKPDS crumbles into dust: in fact the whole edifice of British diabetology, built up on this slender foundation, is looking a bit like the work of Ozymandias. I must say that this has come as a slight shock even to a hardened and vocal sceptic like me; but this subgroup analysis of 6400 participants in the randomised controlled trial is consistent with last week’s meta-analysis in the Archives and with the data from ACCORD. Treating to a target of <130/85 produced the same outcomes as treating to 140/85.

69 We speak of lives cut short by cancer, but in an odd way it works the other way round, according to this study of telomere length and cancer incidence and cancer mortality. The opening sentences of the paper describe the significance of telomere length: “Telomeres are nucleoprotein complexes at the extreme ends of linear chromosomes implicit in the maintenance of chromosomal integrity. Telomeres shorten with each cell cycle and therefore reflect organism aging at a cellular level.” Thus the shorter your telomeres, the less time you have to live. This is demonstrated here in a population study from Bruneck, a German-speaking South Tyrolean town which belongs to Italy. Those with short telomeres had the highest risk of cancer. Now in a German town this would be attributed to the shears of the three Norns, whereas further south it would be attributed to shears of the three Fates.

76 The Rational Clinical Examination series assumes a very high degree of literacy, intelligence and education on the part of its readers; and perseverance, too, as most of these excellent articles set out the evidence in unsparing detail. Why, I even know people who have had resort to skim-reading in some cases. “Can This Patient Read and Understand Written Health Information?” is a great question for this series to address, because it’s one we fail to ask so often. We fail to elicit the physical signs of incomprehension or reading difficulty because we are not looking for them or the patient wants to hide them from us. Just ask “How confident are you in filling out medical forms by yourself?”

NEJM 8 July 2010 Vol 363
109 The TOM trial recruited 209 New England men with a mean age of 74 and limitations in mobility plus low testosterone. Given that there is a definite association between low testosterone and inability to perform vigorous activity (see next paper), might transdermal testosterone restore youthful litheness to these tardy vieillards? Alas, we shall never really know, as the trial was stopped early due to an excess of cardiovascular events in the treatment group within the first six months. Half of the 23 events in this were relatively unimportant but the other half were not, and this study certainly does raise concern that we might be promoting myocardial infarcts and strokes when we try to treat male hypogonadism in the elderly.
123 So should we be trying to identify late-onset hypogonadism in middle-aged and elderly men? This excellent definition-seeking study shows that there is a definite clustering of low testosterone, poor morning erection, low libido, and erectile dysfunction, associated with fatigue and depression. Whether you go looking for it is another matter: I suppose it all depends on what you want to achieve. In monastic circles, the avoidance of wet dreams was a constant anxiety, even mentioned in the great Compline hymn Te lucis ante terminum:
Procul recedant somnia May dreams recede afar
et noctium phantasmata; And phantoms of the night;
hostemque nostrum comprime, And hold back our enemy
ne polluantur corpora. That our bodies may not be polluted.
So for these monks, a low testosterone accompanied by few erections would have been considered a blessing. Whereas for poor Anton Bruckner, the celibate Catholic composer, testosterone levels must have remained painfully high to the end: in his seventies he wore large flannel shorts at night and when he was not climbing bell-towers he would roam the parks proposing marriage to young ladies at random. Finally a young housemaid from Hamburg accepted him, though he died before consummation. Perhaps we old chaps should simply accept whatever falls to our lot in terms of gonadal luck.

136 Now what did I promise you next in the Stent Wars? I do believe it was a battle between zotarolimus and everolimus, though to be honest I am too bored to remember. Anyway, battle has been joined between stents eluting these particular olimusses and so far the result is an exciting draw.

147 Recovery from severe burns to the cornea is limited by the number of stem cells in the limbus, a narrow zone between the cornea and the bulbar conjunctiva. Happily a team of Italians from Milan and Modena has devised a method of harvesting these precious cells and cultivating them on fibrin, so restoring good vision to 77% of the 112 patients they treated with this technique.

156 Mitral regurgitation due to degenerative mitral valve disease isn’t just a topic for exam swots, but a frequent clinical problem well worth updating yourself about with the help of this excellent review. Mitral valve repair is now usually the treatment of choice, with excellent long term success: this largely abolishes the risk of chorda tendina rupture but not of atrial fibrillation. Surgery for the mitral valve reflux of left systolic heart failure has a ten-year mortality of 57%, but that is probably quite low compared with medical treatment alone.

166 In the course of these reviews I’ve taken you through (though perhaps ‘past’ would be a better word) many genomewide association studies and I’m sure that you are finding how much they have improved your assessment of the risk of disease. I certainly am. And so does this article on the subject: we are all agreed that they do not help at all. The author takes us patiently through all the technical details and ends in the plaintive hope that some day all of this may help clinicians. I applaud him for being honest and the New England Journal for letting everybody have this article without charge.

Lancet 10 July 2010 Vol 376
91 A study which would have delighted Sir Geoffrey Keynes (1887-1982) who first tried out limited radiotherapy for breast cancer in the early 1920s. Ninety years later, post-operative radiotherapy is usually delivered in small doses of external beam treatment to the whole breast over several weeks. This trial looked at the effect of a single dose of targeted intraoperative radiotherapy to the immediate environs of the removed early breast cancer, and produced non-inferior outcomes at four years.

103 The CANOE trial was designed by GlaxoSmithKline at a time when rosiglitazone was still a popular drug, and no doubt GSK will point with relief to the fact that at low dosage (2mg) it didn’t do any measurable harm to the 103 Canadians assigned to it in this study. On the contrary, when combined with metformin 500mg b.d. it stopped a good many of them from getting type 2 diabetes. These Canadians were selected for their high risk of crossing the arbitrary threshold of 7mmol/L fasting glucose, so giving them drugs which lowered sugar naturally helped to postpone this. But did it help to postpone anything else? We know that cardiovascular disease and retinopathy refuse to recognise the existence of a glycaemic threshold anyway, and that pushing down sugar of itself can make no difference to these, or even do harm. Metformin is fortunately one drug we know tends to improve real outcomes, but the same can certainly not be said of rosiglitazone. And oddly enough this combination did nothing to preserve beta-cells – as far as we can measure that process. Get out and take a walk: it may do you more good.

112 Exercise will also help you avoid a stroke; alcohol alas will not. Most of the other risk factors for stroke identified by the INTERSTROKE study are the ones you might expect, and the ten main ones account for nearly 90% of the risk. The oddest feature is the role of body mass index: when corrected for other factors, a high BMI actually seems protective, whereas a high waist-to-hip ratio is a substantial risk factor.

124 The two most salient things I’ve learnt from looking into diabetic retinopathy over the last couple of years is (a) that it shows a linear relationship to glycaemia from well below the “diabetic” threshold and (b) it doesn’t greatly matter exactly when you start treating it, provided that visual damage has not occurred. This seminar, by contrast, emphasises the importance of early detection. It discusses the largely negative evidence for tight glycaemic control in relation to eye complications but still comes down heavily in favour of this approach. I am confused.

BMJ 10 July 2010 Vol 341
82 The rotator cuff is one of those body parts which normally works brilliantly well but is a perfect beast when it starts going wrong. This Australian trial tried the effect of a 10-week exercise programme and failed to improve pain while improving function a little bit. If you want all the evidence we have on treating rotator cuff disease, you’d be better off turning to the Annals of Internal Medicine website, where they’ve just posted a big (free) meta-analysis.

83 This study of transdermal and oral hormone replacement therapy and the risk of stroke should boost sales of transdermal HRT, especially low doses. I use the “should” more in a predictive than an advisory way, because I don’t think one can place 100% reliance on case-control studies based the UK GP Research Database. On the other hand, it is reassuring that there seems to be no observed increase in stroke at all with low dose transdermal oestrogen, opposed or not, whereas for high doses and for all oral preparations there is an added risk of 30-40%.

Ann Intern Med 6 July 2010 Vol 153
23 This meta-analysis looks at the trials which have changed practice in recent years towards a lower target haemoglobin in renal patients receiving erythropoietin. It doesn’t matter what stage of renal failure they are at: outcomes are better if you aim for an Hb around 10 rather than one around 13. This doesn’t seem right, but then lots of things in medicine (and real life) are counter-intuitive.

Poem of the Week: Ozymandias by Percy Bysshe Shelley

I met a traveller from an antique land
Who said: “Two vast and trunkless legs of stone
Stand in the desert. Near them on the sand,
Half sunk, a shattered visage lies, whose frown
And wrinkled lip and sneer of cold command
Tell that its sculptor well those passions read
Which yet survive, stamped on these lifeless things,
The hand that mocked them and the heart that fed.
And on the pedestal these words appear:
`My name is Ozymandias, King of Kings:
Look on my works, ye mighty, and despair!’
Nothing beside remains. Round the decay
Of that colossal wreck, boundless and bare,
The lone and level sands stretch far away”.
pub. Jan 1818