11 Feb, 13 | by BMJ Group
JAMA 6 Feb 2013 Vol 309
453 Stone the crows, a great little study from Oz that will change your practice at a stroke. They recruited 212 patients with intermittent claudication who had never had invasive treatment—which immediately made me realise the study couldn’t have been done in America, where at the first twinge of calf pain you get a stent or balloon stuck down your femoral artery. No, these were mostly fine specimens of Australian manhood, mean age 65, getting pains below the level of their shorts if they walked too far, despite the fact that one third of them had never smoked and all of them had normal blood pressure. One half of them were randomized to a well-known drug and after six months they found they could walk four minutes longer before they had to stop. The wonder drug? Ramipril 10mg. This is the kind of trial that makes nobody millions of dollars, but which we should all be doing in our fields of interest. It took just three interested hospitals in Southern Australia.
461 Stone some more crows! I hadn’t realised the first A in JAMA stood for Australian. This time we move northwards to Brisbane where one university research centre recruited 165 patients with lateral epicondylitis and randomized them in 2×2 fashion to receive physiotherapy, corticosteroid injection, or isotonic saline injection (incorrectly described as “placebo injection”). At one year, the corticosteroid group did markedly worse than the others, and physiotherapy seemed to make little difference to anybody. This should not change your practice because it has been known for a long time from other studies that steroid injections prolong the course of tennis elbow; and that physiotherapy, in most contexts, is simply a way of being seen to do something while nature takes its course.
NEJM 7 Feb 2013 Vol 368
503 And now back to the Northern Hemisphere where the big boys live. This study was done in over 30 centres across North America and Europe, and in Iceland, which is somewhere between. Compared with the little fishing boats the Australians used to bring in their useful catch, this looks like an imperial Navy, with battle cruisers and aircraft carriers in full steam. What do they sail forth to capture for the benefit of mankind? “One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a).” Genomic true believers will argue that this is a real step forward, because it is another piece of evidence that this lipoprotein fraction is implicated in valvular calcification. I leave this for you to decide.
513 If you are a major medical journal with a business model that involves large payments for reprints from pharmaceutical companies, then you are bound to love the two wars that ensure your income stream—the Stent Wars (see this week’s Lancet) and the Clotbusting Wars. Given the number of competing products and possible study designs, these two wars alone could go on forever, boring and confusing clinicians and filling the coffers of the NEJM and the Lancet throughout eternity. Rule One for selling reprints is that you make the conclusion of the Abstract as favourable as possible, because this is all that most clinicians read:
“In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for standard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding.” And for your further information: “The study was designed and supervised by the steering committee and was sponsored by Bayer HealthCare Pharmaceuticals and Janssen Research and Development. The members of the steering committee signed confidentiality agreements with the study sponsors. The data were collected and analyzed by the sponsors. All the authors had full access to the data and analyses and contributed to the writing of the manuscript. Editorial assistance was provided by Chameleon Communications.” But even the best chameleon cannot disguise the fact that that rivaroxaban is more than twice as likely as enoxaparin to cause a bleed requiring two or more units of blood by day 10, and similarly by day 35. So an honest Abstract conclusion might read: “In acutely ill medical patients, compared with rivaroxaban, enoxaparin provides equal protection from thromboembolism and is considerably safer.” And the editor of this journal was telling us a few weeks ago that we should not mistrust the reporting of industry trials.
524 Cutaneous leishmaniasis always reminds me of a ferocious, power-dressing Sheffield dermatologist whose update course I attended many years ago. She put up a slide which appeared to show it, and when I gave my opinion, she bellowed, “No! I knew that would catch somebody out!” My incompetence in this area remains the talk of every Sheffield omnibus and tram; and I only venture out of hiding to tell those of you who can actually recognise the condition that you should treat cutaneous leishmaniasis with paromomycin, with or without gentamicin. Nothing much else works. Bye.
551 What we really need is a vaccine for everything. Turning our own, fabulously organized immune system on our enemies is the neatest way to cure any disease, but it has required immense patience and ingenuity to progress from the use of cowpox in the 1770s to the design of new molecules for hidden receptors in the 2010s. I love reading articles about designing tomorrow’s vaccines: this one is fairly broad brush and cautiously optimistic, but best of all the full text is open access.
572 Why do so many people’s pancreatic islet beta cells cease to function, just when they need more insulin because they are getting heavy and insulin resistant? If you could find a way to stop that, you would abolish type 2 diabetes and become one of the medical heroes of the twenty-first century. Here is a short “mechanisms of disease” paper—i.e. labs and mice rather than humans—describing beta cell dedifferentiation. It seems that many beta cells go through a midlife crisis. You know the kind of thing: “I’m stuck here with this person who’s getting fat and makes ever increasing demands on me and I don’t know if I can carry on or even who I am any more.” They probably need counselling.
Lancet 9 Feb 2013 Vol 381
451 Trying to translate research papers into intelligible gobbets of information for jobbing clinicians ever week is certainly good exercise for the ageing brain, but do not imagine that I can be an effective guide to areas of knowledge that I seldom encounter, such as the treatment of rheumatoid arthritis resistant to tumour necrosis factor inhibitors. Like you, I usually read the editorial to put the paper in context, but this week’s on tofacitinib tells me a lot about Janus kinase receptors, but not a lot about where this new drug might fit into the existing arsenal for resistant RA. And when I read the paper, I find the usual sales talk: “Interpretation: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi.” OK; you are Pfizer and this is your chance to get tofacitinib past the licensing authorities. “Employees of the sponsor were involved in study conception, design, and conduct, and in data collection and data analysis. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.” Hmmm. Last week Richard Horton admitted that snuggling up to pharma might not be the best way to get a clear river of medical knowledge. He edits Britain’s most prestigious medical journal and it is time he started thinking of a better way.
461 Not that all non-pharma trials are much better. I utterly fail to understand why this one is published in a leading journal, because it has no endpoints of clinical significance but simply measured the angiographic effect of a paclitaxel eluting balloon as opposed to a non-eluting balloon or a paclitaxel eluting stent in patients who had restenosis after drug-eluting stent implantation. Having some paclitaxel around – whether from the balloon or the stent – seemed to improve the coronary diameters measured 6 months later. “Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups.” So?
468 Why bother comparing your drug with anything if The Lancet will let you trumpet its benefits without a comparator? Gilead Sciences started off in 2005 with a trial of its once-daily preparation of tenofovir disoproxil fumarate versus once-daily adefovir dipivoxil for 48 weeks, and demonstrated to its own satisfaction that tenofovir DF was more effective than adefovir in terms of viral suppression and relief of histological inflammation. Patients were then switched to open-label tenofovir and followed up: “In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis” says the Interpretation. Oh, and in case you hadn’t guessed, “The sponsors of the study designed the study, gathered the data, and did the analyses. All authors had access to all the data from the study and participated equally in the decision to submit for publication.” Are there better drugs out there for hepatitis B? I’m afraid I have no idea. And would I expect these guys to tell me?
496 “Pneumonia tends to affect individuals who are also at high cardiovascular risk. Results of recent studies show that about a quarter of adults admitted to hospital with pneumonia develop a major acute cardiac complication during their hospital stay, which is associated with a 60% increase in short-term mortality.” Golly, somebody has finally twigged that the heart and the lungs are joined up to each other and live in this space called the chest, or thorax. This could have major implications. We could start thinking of providing services for elderly breathless patients rather than making them wander from chest physicians to cardiologists and back again: we could tackle the problem of the post-hospital syndrome by attending to the cardiovascular risks of chest infections and the right ventricular contribution to heart failure; we could even ask patients what their main problems are and whether they are sufficiently addressed to make them feel safe at home. But all this requires a level of genius far beyond the reach of any known health service.
BMJ 9 Feb 2013 Vol 346
Corporate crime in the pharmaceutical industry IS THERE A CURE? asks the cover of the BMJ. A rather vague answer comes in an opening editorial, a much more focussed one in a great piece on Tamiflu by Harlan Krumholz and colleagues, and a suitably radical one from the indefatigable Peter Gøtzsche. Until crime ceases to pay, and individuals are held to account, don’t expect any change in banking, or tobacco, or arms sales, or in the pharmaceutical industry.
The BMJ was lucky to scoop this paper based on retrieved follow-up data from the Sydney Diet Heart Study (1966-73) which recruited men who had had coronary events and successfully lowered their cholesterol by substituting safflower oil for animal fat. This raised mortality by a third over five years. Beware omega 6 linoleic acid which abounds in safflower oil and constitutes more than 50% of sunflower, cottonseed, corn and soy oils. Stick to healthy butter, lard, goose fat and olive oil, as civilised people have done through the centuries.
I never quite know what to do for the best when investigating urinary tract infection in children, except that I would rather they didn’t have to undergo the physical and psychological cruelty of micturating cystourethrography. Most don’t: this Rational Imaging article is detailed and clear. However, the case example is unfortunate: a five month old boy who has a single UTI and goes through ultrasound, micturition cystourethrography, and finally DMSA scanning to prove that he doesn’t have scarring—and who has no further episodes of UTI.
Plant of the Week: Corylus avellana
The common hazel can be a magical plant at this time of year, if you know of a wood where snowdrops grow beneath, and the hazels can catch the sun on their abundant long creamy green catkins.
Catkin-lovers can also grow Garrya elliptica, which is a very large evergreen shrub of a somewhat municipal aspect. It is almost too fit for purpose: the leaves are dark and twisted and shiny, and the catkins are long and fat and grey and superabundant. Let other people plant this monster, either free standing or trained against a wall.
If I were to seek catkins, I would go for Corylus or a related species. The one we actually have is Corylus maxima “Purpurea,” a filbert yielding good nuts in the autumn and purplish catkins in late winter. By systematic mistreatment we have managed to keep it quite small. This is essential, or you will have a tousled mass of purple leaves louring over your garden all season long.
All season… Yes, we have all the gardening season to look forward to now.