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Written weekly by Richard Lehman, Journal Watch provides a personal comment on articles from the main medical journals selected for their interest to doctors (and a few others!)
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JAMA 15 May 2013 Vol 309
2016 I got into a bit of a muddle with this paper, but I blame JAMA. Let me test you out: the abstract says “Long-term follow-up of the randomized, masked 2-year Colpopexy and Urinary Reduction Efforts (CARE) trial of women with stress continence who underwent abdominal sacrocolpopexy between 2002 and 2005 for symptomatic POP and also received either concomitant Burch urethropexy or no urethropexy.” Then in the first section of the full text the cohort is described as from a “multicentre, randomized, masked trial in women without stress urinary incontinence (SUI).” Because I’ve never before heard women described as being “with stress continence,” and then randomized to incontinence surgery, my mind supplied the prefix “in.” Did yours? Anyway, let’s get this quite clear: the women in this study had pelvic organ prolapse without stress incontinence and they all got a procedure called abdominal sacrocolpopexy, by which the vaginal vault is fixed to the sacral anterior longitudinal ligament. Half of them also got the procedure called Burch urethropexy to support the urethra and hopefully prevent stress incontinence. They were asleep during the procedures and not told whether or not they had the Burch procedure. Stay with me - we are nearly there. At seven years, a lot of the sacrocolpopexy procedures had come adrift anatomically and the women who had the concomitant Burch procedure had less stress incontinence. So are you now clear about the message of this paper for patients and general clinicians? I can’t say that I am, but it is a nice piece of work and I hope that it will be of interest to urogynaecologists and those in the IDEAL collaboration who study surgical trial methods.
2035 The older Rational Clinical Examination articles include some classics of the medical literature, but alas this new one is not among them. It was doomed from the start: “Do Findings on Routine Examination Identify Patients at Risk for Primary Open-Angle Glaucoma” - now what would your answer be? Send them to a doctor who can examine eyes. Correct. “The best available data support examination by an ophthalmologist as the most accurate way to detect glaucoma.”
NEJM 16 May 2013 Vol 368
This week’s NEJM is dominated by hepatitis C (HCV) and a new drug called sofosbuvir. So - why the fuss about sofosbuvir? I think you really have to be a hepatitis C expert to understand, so let me try and become one for your sakes, since the journal provides areview article designed for that very purpose, and an editorial which I am sure to understand once I have read the review.
Some hours later. Sorry folks, this isn’t really working. The level of technical detail defies any attempt at summarization and things are changing by the week. Deaths from HCV have now overtaken deaths from HIV in the USA, despite the staggering rate of progress in knowledge and therapy. Here are some soundbites: “The speed of development of drugs to treat HCV infection is unprecedented. The publication of clinical data with respect to sofosbuvir comes only 3 years after the publication of the chemical discovery of the compound.” “Only 20 years after the discovery of the hepatitis C virus (HCV), a cure is now likely for most people affected by this chronic infection, which carries a substantial disease burden, not only in the United States but also worldwide.”
Progress in HCV therapy is a perfect showcase for what modern pharma can do when faced with a huge new challenge and market. Although HCV is nearly as elusive a target as HIV, laboratories are providing drugs targeted at new mechanisms almost every month, and bringing them to trial with unprecedented speed. The US Food and Drug Administration (FDA) has helped by reducing its standard for licensing from 24 to 12 weeks of sustained viral suppression. The viral gene gnomes have helped by identifying 6 major HCV genotypes. This is therapeutic science at its swiftest and sexiest: and patients are certainly benefitting.
I can’t really tell you if the fuss about sofosbuvir is warranted: the hope is that it will do away with the need for interferon in many patients. But next week we may get evenbettervir which hits more subtypes, and finally bigbuxovir which sweeps the market and makes billions for its manufacturer. And then what? Lots of head-to-head trials on a bewildering array of combinations; more attention to long-term safety issues; cost-benefit calculations which change every couple of weeks with the pricing of the drugs; and above all, treatment regimens which are inaccessible to the great majority of those who need them worldwide. It would be sad, but I suspect true, if the quote I gave above should really read, “a cure is now likely for most people affected by this chronic infection, provided they have the means to afford it or someone else is paying.”
Lancet 18 May 2013 Vol 381
This week’s Lancet is given over entirely to interventional and observational research and analysis from the resource-poor world. The Lancet’s leadership in this is something the world should be grateful for, even though articles are all hidden behind an Elsevier paywall. I’ll try to give you a flavour of some of them.
Saving Newborn Lives is the name of one of the funders of a big cluster-randomized trialin rural Malawi; it was aimed at doing just that, and succeeded. The interventions were either the formation of women’s groups, or the deployment of peer counsellors, or both, in a 2×2 factorial design. The end-points were maternal mortality, infant mortality, and the uptake of breastfeeding. The biggest mortality differences seemed to come from the women’s groups, but the counsellors did well too.
That’s the same message as emerges from a systematic review of women’s groups practising participatory learning and action, compared with usual care, on birth outcomes in low-resource settings. “With the participation of at least a third of pregnant women and adequate population coverage, women’s groups practising participatory learning and action are a cost-effective strategy to improve maternal and neonatal survival in low-resource settings.”
But beyond this basic stage of disseminating health information, it’s not all good news. The enormous WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS) looks with dismay at the maternal and neonatal outcomes of health facilities in Africa, Asia, Latin America, and the Middle East that dealt with at least 1000 childbirths per year and had the capacity to provide caesarean section. “High coverage of essential interventions did not imply reduced maternal mortality in the health-care facilities we studied. If substantial reductions in maternal mortality are to be achieved, universal coverage of life-saving interventions need to be matched with comprehensive emergency care and overall improvements in the quality of maternal health care.”
Control of population growth is still the human race’s most important priority, in my opinion. That means universal access to contraception, and the next survey seeks to find out how far that is being achieved. The two authors have done a heroic job going through the national survey data available for 2003, 2008, and 2012. The irony is that the number of childbearing women is increasing rapidly and matching the increase in provision of contraception.
BMJ 18 May 2013 Vol 346
Let the Patient Revolution Begin: a great editorial by some great people. The only possible ray of hope amongst the destruction of the NHS in general, and primary care in particular, is that patients will say “Enough is enough. We own this service and you must listen to us and make it work for us.” And the same could even apply in the USA, one day. I spent my whole professional career trying to provide continuity of care and trying to promote a vision of locally available services based on close linkages with specialist providers. But despite all the rhetoric, every political and managerial development has moved the NHS further from that goal. In a piece ostensibly about multimorbidity, Martin Roland joins the chorus which blames GPs for fragmenting the care of patients: as if we had much choice in the matter. But what little choice we do have, we must use. Our efforts will be entirely futile unless we really create a partnership with the people we serve, and shape our efforts according to their needs and not the convenience of managers and providers.
Two injections of 3ml of autologous blood around the mid-portion of the Achilles tendon: what’s that meant to do? It’s meant to help the resolution of mid-portion tendinopathy: and it seems that this sort of procedure has caught on in many circles (see editorial). This Australian trial confirms that it is a bloody silly idea.
Are you a man? Are you in your early sixties? Don’t have any prostate symptoms? Well, my friend, let me tell you something: the chances are that before very long, your stream won’t be so good and you’ll be getting up at night like me. Just let me do a rectal examination. There, you see, your prostate feels quite big. So don’t wait for symptoms to happen: take dutasteride now! Proven to REDUCE the onset of prostate symptoms over four years in men with benign enlargement. Oh, and you can put your trousers back on now.
You’ll be tired by now of me banging on about the need for long term proof of safety and a reduction in patient important adverse events before awarding a licence for sugar lowering drugs in type 2 diabetes. Sitagliptin is one of a group of drugs (DPP 4 inhibitors) which is coming under close scrutiny for possible harms to the pancreas; following short-term trials, it was licensed in 2006 under the brand name of Januvia. Here is a survey of a large US provider database looking at outcomes over 2.5 years. They detect no increase in acute pancreatitis and a neutral effect on all cause hospital admission and mortality. But that is not the end of the matter, as the editorial explains. It’s a well-conducted study, but in a drug that may be taken for decades, insufficient to allay all concerns.
JAMA Intern Med 13 May 2013 Vol 173
People who are given corticosteroids often have conditions that increase the risk of venous thromboembolism (VTE), so how can you tell if the corticosteroids themselves cause VTE, or whether it’s all confounding by indication, to use the EBM jargon? It’s something the authors of this Denmark-wide case-control study have considered carefully. Filling in a prescription for steroids in Denmark is associated with a doubling in the risk of VTE. Confronting the confounding issue, they respond, “we consider a biological mechanism likely because the association followed a clear temporal gradient, persisted after adjustment for indicators of severity of underlying disease, and existed also for noninflammatory conditions.”
If you use a non-benzodiazepine hypnotic (a “Z-drug”) for nursing home patients, you will increase their chance of a hip fracture. “New users and residents having mild to moderate cognitive impairment or requiring limited assistance with transfers may be most vulnerable to the use of these drugs.” Sometimes life is exactly as you expect.
Lock ‘em up and stop them having any cigs: that’ll cure them. But in fact the fascist method of smoking cessation is almost uniformly unsuccessful. Prisoners released from American jails where they were forced to give up smoking are back smoking regularly at 3 months in 98% of cases, male and female. Those offered the WISE intervention,described in this study, sustained a quit rate of 12% at 3 months. It’s a sad, mad world.
Plant of the Week: Pawlonia fargesii
After praising the amazing Chinese plant finds of the French missionaries Père Delavay and Père David, I must now complete the story with Père Paul Guillaume Farges. Although he was sent to China at much the same time as his illustrious confrères, it took him over 20 years to get posted to Chongquing where a priest could fulfil his true vocation to collect plants as well as to feed the faint and hungry heathen with the riches of the word. Unfortunately for Farges, by that time the best Chinese plants had been spoken for by others; so his efforts (amounting to 4000 plants) are remembered by relatively few well known species, though he has a whole genus of bamboos named after him.
The pawlonia is a show stopping tree in full flower, with huge upright panicles of scented lilac-blue foxglove blooms. Its northern limit in England seems to be in the middle of Oxfordshire. A lovely example has flowered for decades in Oxford Botanic Garden, whereas two examples (one mine) grew tall and flowered for a few years just 25 miles to the north, and then gave up in disgust at the lack of sun and the damp of our summers and winters. Mine was labelled fargesii but looked exactly the same as the speciestomentosa: and in fact the two are now considered to be essentially the same plant. Poor Père Farges gets third prize again: now no longer his own species, but just a variety.
JAMA 8 May 2013 Vol 309
1903 When an implanted cardioverter defibrillator goes off inside you, you are sure to feel deeply shocked: whereas, for others, watching you drop dead might be even more shocking. One needs to strike a balance. That was the purpose of the ADVANCE III (Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III) trial. Essentially this was a gamble on how many ventricular tachycardia beats are allowed to happen before the device fired: with current devices it is usually 18-24, whereas in this trial half the patients got a newly programmed device which counts to 30-40. They stayed alive as much, didn't have more syncopal episodes, and had a third fewer shocks in the first year.
1912 I thought that every human being in the state of nature carried Helicobacter pylori, but I was wrong: about 5-10% of the human race never harbour the bug, no matter how much they are exposed to it. This paper reports on two studies which identify the genotypes of these helicobactrophobic individuals in Pomerania and in Rotterdam. The investigators confess that they cannot think of any use for this knowledge at present; but in the great scheme of things it may come in handy one day; which no doubt is why JAMA decided to share it with us.
NEJM 9 May 2013 Vol 368
1771 Haematological cancer is not my specialty, or yours, in all likelihood. We don't have to decide when to give platelet transfusions, but those who do have found over the years that they can safely wait until the platelet count has gone down to 10×109 and then give half as many platelets as they used to. The next step would be to give none at all until a bleeding event occurs, and that was the strategy tested in this Australo-British trial. But it was a step too far: the rate of serious bleeding in the no-prophylaxis group was only modestly higher (by 8%) but their bleeds came sooner and lasted longer.
1791 I saw the title and expected a good observational study: Respiratory Syncytial Virus and Recurrent Wheeze in Healthy Preterm Infants. And there is certainly plenty of good observational data in this study; but essentially it is a trial of palivizumab, an anti-RSV agent manufactured by Abbott, in preterm infants, with a primary outcome consisting of the total number of parent-reported wheezing days in the first year of life. So the title should really have been "Palivizumab injections to prevent wheezing in the first year after preterm birth." I don't know if reprint-selling disease has spread to the titles ofNEJM articles, but it looks that way to me: we'll never know how many copies of this paper get bought up by Abbott or how they might be used to promote sales of palivizumab, because the NEJM considers that commercially confidential. The economics of palivizumab were discussed in a BMJ piece in 2009: a course of RSV prophylaxis costs between £3-5K in the UK. It's estimated that at least 60% of babies get RSV in the first year of life. In the great majority it is a mild illness, though some get bronchiolitis and may then wheeze after each subsequent upper respiratory tract infection; by the age of three hardly any do. So it's hard to put a price on a 60% reduction in first-year wheezing days: a happy outcome, certainly - but worth spending £3-5K on every baby born at 33-35 weeks' gestation?
1800 They're at it again! Crunching up thousands of tons of lovely oily fish and turning them into capsules of n-3 fatty acids. These were then fed to Italian "men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil)." Maybe 1G of olive oil is just a placebo: certainly for an Italian. Anyway, there was no difference at 5 years. To derive any protection, you have to eat the fish as well as the oils. Turbot is the best fish for n-3 fatty acids, I'm told: excellent as steaks or fillets fried in butter and served with a sauce of reduced cream, white wine and morels (or since you probably lack morels, some fresh chopped sorrel at the last minute); or just a simple hollandaise. The point of all fish is the butter that goes with them. There are those who assert that the quantity of butter should equal the quantity of fish, but I think that this should be left to the conscience of the individual believer.
1817 Here's a really comprehensive review of enteropathogens and chronic illness in returning travellers, which makes you wonder what we're missing in some of these unfortunates. The GeoSentinel Surveillance Network gathered data on 25,867 returned travellers over a 9-year period (from 1996 to 2005). "Of the 2902 clinically significant pathogens that were isolated, approximately 65% were parasitic, 31% bacterial, and 3% viral. Six organisms (giardia, campylobacter, Entamoeba histolytica, shigella, strongyloides, and salmonella species) accounted for 70% of the gastrointestinal burden." My goodness, that still leaves 2,896 other pathogens in travellers' diarrhoea, which is more than I thought existed in the Universe. Respect!
Lancet 11 May 2013 Vol 381
1627 Psychiatry is in a permanent mess, alternating between dogma and self-doubt. A century ago, it was the unconscious mind (as expounded by Middle European authority figures) which promised to explain everything: now it is going to be genomics. In the meantime, this is a bad world to be mad in. If you are labelled psychotic, you are required to conform to the latest fashion in treatment: this used to be compulsory admission under Section 17 of the Mental Health Act, but now it is increasingly a compulsory treatment order in the community. The OCTET investigators postulated that patients with a diagnosis of psychosis discharged from hospital on CTOs would have a lower rate of readmission over 12 months than those discharged on the pre-existing Section 17 leave of absence. But that did not happen. "In well coordinated mental health services the imposition of compulsory supervision does not reduce the rate of readmission of psychotic patients. We found no support in terms of any reduction in overall hospital admission to justify the significant curtailment of patients' personal liberty."
1634 The next trial reported was an attempt to measure the effect of anticipatory shared decision making by people with serious mental illness. It aimed to compare the effectiveness of Joint Crisis Plans (JCPs) with treatment as usual. "The JCP is a negotiated statement by a patient of treatment preferences for any future psychiatric emergency, when he or she might be unable to express clear views." This sounds like a really good idea, and a strategy that should reduce the need for compulsory admission - but in this trial it didn't. The investigators seem pretty peeved: so much so that they blame the participating teams. "Our findings are inconsistent with two earlier JCP studies, and show that the JCP is not significantly more effective than treatment as usual. There is evidence to suggest the JCPs were not fully implemented in all study sites, and were combined with routine clinical review meetings which did not actively incorporate patients' preferences. The study therefore raises important questions about implementing new interventions in routine clinical practice."
BMJ 11 May 2013 Vol 346
The best news this week comes from Australia, and it is awesome: quadrivalent human papillomavirus vaccination of young women in Victoria caused an 82% drop in genital warts in those offered vaccination, and a similar drop in young men of the same age group (who hadn't been vaccinated). In the women who were actually vaccinated in 2011, genital warts did not occur at all. As if to drive home the point, no significant decline was observed in older women or men, non-resident young women, or men who have sex with men. As the editorial puts it, "These are exciting times in the science of HPV and the world can confidently look forward to the virtual elimination of genital warts, recurrent laryngeal papilloma, most genital cancers, and some 60% of head and neck cancers." News doesn't often come better than that.
Lordy, lordy, how some people never get it about screening. It's not that I don't recognize the thoughtfulness and intelligence of the 12 authors who wrote this paper about the Malmö Preventive Project in Sweden, which used data from frozen sera to show that PSA testing at 40-55 can identify a cohort of men at high risk of metastatic prostate cancer several decades later. They build up their argument carefully and acknowledge the problems of harm from overdiagnosis, only to conclude that men with low initial PSAs will need another three tests to be sure they are still at low risk. Ugh. Where is any evidence that this will reduce overdiagnosis and affect all-cause mortality? Until we have a test that tells us reliably if someone has the kind of prostate cancer that might cause death in the next few years, and we have an intervention that prevents this, we should continue to discourage all testing; or else castrate all men at the age of 60.
This reminds me of an anecdote I have just read in Michael O'Donnell's lovely new book,The Barefaced Doctor. He describes a Dublin surgeon of the 1950s whose idea of patient communication was to walk down the ward calling out the name of the procedure each person should expect: "In those days elderly men with prostatic cancer were offered treatment by physical rather than hormonal castration and one morning the surgeon went on his rounds, declaiming his intentions in his usual way.
'Laparotomy... castration... appendicectomy...'
'Hang on a second, sir,' said patient number two with unforgivable impertinence. 'This castration business? What exactly would that involve?'
The surgeon, perplexed by the interruption, barked a reply:
'A simple matter, my man. We'll just remove your testicles. At your age, they're no use to you.'
'Oh, I know that, sir,' said the man. 'But they are kind of... dressy.'"
Order your copy now: there is nothing else like it in this dull age.
A very useful follow-up study of 2,411 Danish women following breast cancer treatment in 2005-6 finds that a large number experience pain and that this is least in the group who have mastectomy and lymph node biopsy only (22%), and highest in those who have breast conserving surgery combined with biopsy and chemo and radiotherapy (53%). This would imply that modern treatment modalities are actually increasing the prevalence of long-term pain. The prevalence of pain in the cohort fell between 2008 and 2012, but interestingly the traffic was not all one-way: 36% of those with pain in the earlier survey now had none, but 15% of those who had none earlier now had some.
The high standard of BMJ Clinical Reviews continues with an exceptionally useful account of acne and its treatment. Read and learn: if you prescribe oral antibiotics, always co-prescribe a topical retinoid or benzoyl peroxide. Remember the adverse effects of many treatments and warn your patients: and also tell them to be patient, as nothing works immediately.
Ann Intern Med 7 May 2013 Vol 158
676 Courtesy of the Annals, you can read the whole of a big systematic review of management strategies for asymptomatic carotid stenosis. Golly, what a mess. "Studies defined asymptomatic status heterogeneously. Participants in RCTs did not receive best available medical therapy... Future RCTs of asymptomatic carotid artery stenosis should explore whether revascularization interventions provide benefit to patients treated by best-available medical therapy." Correct me if I'm wrong, but doesn't that prove that all the 47 studies analysed here were actually unethical, because they tell us nothing about how to manage asymptomatic carotid stenosis and did not give patients an adequate control intervention?
Plant of the Week: Corydalis flexuosa "Père David"
Last week I told you a bit about the work of the French missionary botanist Père Delavay, and this week it is the turn of the arguably even greater Père Armand David, who was ordained in 1862 and shortly afterwards sent to Beijing by the Congregation of the Mission. He set up a Museum of Natural History there, concentrating on zoology rather than botany, and his name is perhaps best remembered for Père David's Deer, a beautiful ruminant which had nearly died out when he first discovered it in the gardens of the Emperor. He also told the West for the first time about the Giant Panda and 63 other new animal species, and 65 new species of birds: in botany, he introduced 52 new species of rhododendron alone, plus the wonderful dove tree that bears his name, and a host of smaller plants.
The corydalis is a lovely tuft of finely cut brown-purple foliage with an abundance of long tubular flowers of the purest sky blue. Its main flowering season is about now, but it often carries a few a bit later. It has the habit of dying back in the summer, which can be a bit unnerving. It also has the habit of dying for good if allowed to dry out, or if exposed to too much sun. So plant it in a damp shady place and think of Père David, a lanky man with mandarin moustaches, telling his rosary among the beasts and flowers of his new Eden.
JAMA 1 May 2013 Vol 309
This week's JAMA is devoted to child health. This was a mistake, because although children are generally interesting, health generally is not. A study from Quebec tries out various doses of vitamin D in babies and finds you can only get to a reliably high value by using doses which might cause hypercalcaemia. I'm not sure how many generalist readers need to know this. Likewise it's faintly interesting that two doses of human papillomavirus vaccine given between the ages of 9 and 13 may give the same immunogenicity as three given between 16 and 26, but as we don't definitely know how long this lasts from the trial, nobody is going to change practice. But among the skim-and-flick-past articles there is one important one, which brings good news for the parents of very premature babies.
1810 I am used to reporting depressing figures about premature babies, but this population-based prospective cohort of consecutive extremely preterm infants born before 27 weeks of gestation in Sweden between 2004 and 2007 is different. Admittedly 31% of them did not survive to the age of two and a half, but those who did were mostly in reasonable shape, which the investigators attribute to active perinatal care. "Of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability and neurodevelopmental outcome improved with each week of gestational age. These results are relevant for clinicians counselling families facing extremely preterm birth."
NEJM 2 May 2013 Vol 368
1675 To my mind, the words "meniscal tear" conjure up Monday morning at the surgery, with young men hobbling in to report crunching and swelling of their knee after a hard game of football on Saturday afternoon. The METEOR trial, however, was not interested in young amateur sportsmen: the mean age of the participants was 58 years, and 58% were female. Now at that age, about half of the knees you put through an MRI scanner will show meniscal tears of some sort, and in people with knee pain due to osteoarthritis, a judgment has to be made whether to interfere with the cartilage. If there is a financial gain to be made by interference, then you can expect arthroscopic trimming to follow swiftly. The alternative is physiotherapy, which was employed as a sophisticated-sounding package in the trial: participants were randomised to this or a prespecified range of arthroscopic procedures. A very worthy effort: undoubtedly there are far too many arthroscopic knee procedures carried out in the USA; and this trial showed similar outcomes in the two groups at 6 months. But it is a devil of a trial to generalize from. Of 14,430 patients assessed, 12,008 did not meet the trial criteria, and only 351 underwent randomization. Of these, 30% of the physio group had crossed over to surgery during the six months. So the intention-to-treat analysis does not really carry much weight, and I suspect orthopaedic surgeons will carry on doing whatever pays for the best and fastest car.
1695 Now for a trial which takes you straight to the heart of British general practice, though sadly no GPs seem to have been directly involved. The patients in PATCH-1 had been referred to UK dermatology departments for recurrent leg cellulitis, or else responded to direct advertising: they were randomised for receive either phenoxymethylpenicillin 250mg bd or a matching placebo. Those who got the penicillin suffered fewer recurrences, with a NNT of 5. When they stopped the penicillin, they got the same number of recurrences as the other group. This is useful knowledge, but it may not necessarily apply to your typical old lady visited by the district nurse. The average age of the participants was 58, and I am baffled at the failure to specify how many of them had diabetes. The choice of poorly absorbed straight penicillin as prophylaxis is also a bit odd: perhaps we need a PATCH-2 study using, dare I say it, twice weekly low-dose azithromycin.
1704 The reason I mention azithromycin is because it has already been shown to prevent respiratory infections in COPD, and overall, I think the evidence points to low doses being harmless, even in the presence of cardiovascular risk factors. The QT-prolongation/sudden death risks seem to be related to peak dosing, according to the discussion piece which opens this week's NEJM. But it's a tangled debate, with only observational evidence to go by. A Tennessee Medicaid study showed an extra cardiovascular death for every 21,000 patients prescribed azithromycin instead of amoxicillin. The latest study from Denmark, published here, shows no added risk from a five-day course in the whole of the population aged 18 to 64, but you could argue forever about comparators (it was Pen V again here), propensity scores and confounding by indication.
Lancet 4 May 2013 Vol 381
1532 The Lancet offers thin pickings this week. Here Zeke Emanuel, one of a famous trio of pugnacious brothers, criticizes the Helsinki Declaration, which will be fifty years old this year. He is right: it is a sprawly and incoherent document, aiming to set down the ethical principles of medical research, but straying into other areas, and badly neutered by political interference. I have actually read all the versions, and also their predecessor, the Nuremberg Code, while preparing a piece on the ethics of non-disclosure of human trials. We need a completely new version of the Declaration, with central insistence on the disclosure of all data from every human study, and penalties for failure to do so. Now the AllTrials petition has just reached 50,000 signatories - if you are not among them, we will forgive and embrace you if click here and sign at once.
1541 Gosh and golly: should I use tocilizumab monotherapy or adalimumab monotherapy for the treatment of rheumatoid arthritis? The answer, in most cases, is that you should use neither, but try methotrexate in everyone, on its own or with a "biological."This head-to-head trial recruited patients with RA said to be intolerant to methotrexate or to have no response to it. You have to wonder how consistently these criteria were applied to the 326 patients recruited from 76 centres in 15 countries in North and South America, Australasia, and Europe. But anyway: Hoffmann la Roche declare a win for their product tocilizumab, an inhibitor of interleukin 6 receptor signalling, versus adalimumab, which is an antibody against TNFα. I defy anybody to be sure that this is not just an artefact of the doses used, or to know how to fit this in to the clinical management of RA:the editorial has a good try, but ties itself in knots. Gosh and golly: I'm glad I'm not a rheumatologist.
BMJ 4 May 2013 Vol 346
Orlistat, which interferes with fat absorption in the bowel, is the only drug treatment for obesity available in the UK and many other countries. The subtitle of the editorial which accompanies this article says that it is "still a useful option for some obese patients," though that is not my experience. "All it did is make me fart for England" is one patient comment I remember; and since pétomania has not yet been adopted as an Olympic sport, this somewhat narrows its clinical usefulness. It may - or may not - sometimes cause liver inflammation too. The conclusion of this UK CPRD based study does a bit of bet-hedging: "The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug."
This next study was carried out in Australia using data from Massachusetts and Tokyo, and it shows that you don't need to go remeasuring cardiovascular risk more than about every 10 years in low-risk groups. This is a really useful analysis. In higher-risk groups, measure more often if you have decided not to treat: above all, involve the patient in making any decisions, and help all smokers to stop.
I went to a course on systematic reviewing at about the time the Cochrane collaboration was set up, and haven't had many refreshers since; but it strikes me as a difficult and in many ways subjective activity, despite everyone's best efforts to make it a science. I don't think it will ever come into its own until the raw individual patient data and all the meta-data for all trials are available; and then it will become such a massive and specialised effort that perhaps only two centres in the world will have the support and the expertise to do it properly. But I digress, and perhaps most readers don't really care for these technical details: but they should, because this is the foundation for clinical decision-making, and when you have cancer you will be glad that somebody somewhere has done the job properly. Here's a paper showing that it can be very hard to judge bias from the published versions of cancer trials: babies may be thrown out with bathwater, or the opposite, if that is possible. I am getting into deep problems with entropy, water, and babies here. Let the investigators speak for themselves:
"Overall, 23 trials (23%) were assessed as low risk of bias based on publications alone; however, with additional information, 66 trials (66%) were classified as low risk of bias. Had the 13 meta-analyses included only those trials at low (or lower) risk of bias (as recommended in the Cochrane Handbook), and if assessments were based on publications alone, five meta-analyses (38%) could not be undertaken, because none of the included trials were judged to be at low risk of bias." Simples.
I've already made a joke at the expense of orthopaedic surgeons in this review, and indeed it's pretty impossible to write a blog like this without some recourse to this rich tradition of medical scorn. So I commend to your attention this article on adolescent idiopathic scoliosis: just look at those diagrams: these spine surgeons deserve respect. Orthopaedics at its best does more direct good than almost any other medical specialty.
Plant of the Week: Osmanthus delavayi
I've left it slightly late to celebrate this excellent shrub, since the flowers on ours are already beginning to brown off a bit. "Osmanthus" means scented flower, and the rich fresh scent of this shrub and its commoner child O x burkwoodii are among the delights of early spring, when the sun comes out to warm them.
This delicious osmanthus is named for Jean Marie Delavay (1834-1895), who was sent as a missionary to western China in 1867 by the Missions Etrangères de Paris. His harvest of souls is not known, but cannot have equalled the harvest of 200,000 botanical specimens he sent back to Franchet in Paris. Unfortunately he did not send back many entire plants, but those that he did are generally magnificent. Anything with the specific name of delavayi is worth having if you can grow it.
Father Delavay's osmanthus is usually grown as a medium-sized wall shrub and is said to be slightly susceptible to frosting. But while we have lost several nice little shrubs to frost in this protracted winter, O delavayi grown by a flimsy wooden fence has no visible damage at all, and has flowered abundantly. Left to its own devices, it affects a sprawling elegance, with arches of small dark evergreen leaves; but it is tougher than it looks, and if you want to train it into a tighter shape, it will respond to regular discipline from the secateurs. Definitely among the top ten evergreen garden plants.
Page last edited: 20 May 2013